Compositions and methods relating to salts of specialized pro-resolving mediators

ABSTRACT

The present invention relates to compounds of Formulas I-IV, which are salts of special lipid mediators of inflammation, compositions containing same, and methods of using same in the treatment of various diseases and disorders characterized by chronic or excessive inflammation, or both.

FIELD OF THE INVENTION

The present invention relates to new chemical entities which are saltforms of lipid molecules, and their use.

BACKGROUND OF THE INVENTION

The inflammatory response in animal tissues has two phases, initiationand resolution. At the cellular level, initiation is characterized byedema and the accumulation of immune cells such as neutrophils,monocytes, and macrophages. The initiation phase of the inflammatoryresponse has long been recognized as an active process driven bymetabolites of arachidonic acid such as the prostaglandins PGE₂ andPGD₂, which are chemo-attractants for eosinophils, neutrophils andmonocytes, and the leukotrienes, especially LTB₄ which elicit adhesion,chemotaxis, and aggregation of leukocytes. In order for the inflamedtissue to return to a healthy state, the excess inflammatory cells,cellular debris, and other remnants of the host defense and any invadingmicroorganisms must be cleared. This ‘resolution’ phase of theinflammatory response was for many years believed to be a passiveprocess, the result of the dilution of the chemo-attractants of theinitiation phase. Today, resolution of inflammation is recognized as anactive process, driven by various molecules. For example, protectins andresolvins are autacoids produced locally at the site of inflammation.They assist in resolving inflammation by recruiting non-inflammatorymonocytes which differentiate into macrophages that can remove excessneutrophils and cellular debris. These molecules are part of a class of‘specialized pro-resolving mediators’ (“SPMs”) of inflammation. OtherSPMs include lipoxins, aspirin-triggered resolvins and aspirin-triggeredprotectins. See Serhan et al., “Lipid Mediators of Inflammation”, ColdSpring Harb Perspect Biol 2015; 7:a016311.

Excessive inflammation is widely recognized as a unifying component inmany chronic diseases including vascular diseases, metabolic diseases,and neurological diseases. See e.g., Serhan, C. N., Nature 2014510:92-101. Accordingly, the ability to resolve excessive inflammationis of importance to human and animal health.

Researchers have established a role for various SPMs in numerous diseasemodels, including those relating to Alzheimer's disease, burn wounds,chronic pancreatitis, diabetic wounds, dermatitis, pulmonaryinflammation, peripheral nerve injury, obesity, allergic airwayresponse, amyotrophic lateral sclerosis, acute lung injury, fibrosis,bacterial infection, peritonitis, dry eye, tissue regeneration, pain,adipose tissue inflammation, localized aggressive periodontitis,colitis, temporomandibularjoint inflammation, arthritis, postoperativepain, postsurgical cognitive decline, endotoxin shock, HSV-keratitis,allograft rejection, heart ischemia, bacterial pneumonia, cigarettesmoke-induced lung inflammation, vascular inflammation, fibromyalgia,and vagotomy. See e.g., Serhan et al., “Lipid Mediators ofInflammation”, Cold Spring Harb Perspect Biol 2015; 7:a016311. U.S. Pat.Nos. 8,008,282 and 6,627,658 describe lipoxin analogs and their use asinhibitors of angiogenesis. U.S. Pat. Nos. 5,441,951, 5,648,512,6,048,897, 6,316,648, 6,569,075, 6,887,901, 7,288,569, and 7,294,728,7,741,369, and 7,741,369 describe lipoxin compounds and their use intreating cell proliferative disorders. U.S. Pat. No. 8,119,691 describeslipoxins and aspirin triggered lipoxins and their analogs in thetreatment of asthma and inflammatory airway disease.

US 20060293288 describes the use of resolvins to treat gastrointestinalinflammation and diseases such as ulcerative colitis, Crohn's disease,infectious enteritis, antibiotic associative diarrhea, clostridiumdifficile colitis, microscopic or lymphocytic colitis, collagenouscolitis, colon polyps, familial polyps, familial polyposis syndrome,Gardner's Syndrome, helicobacter pylori, irritable bowel syndrome,nonspecific diarrheal illnesses, and intestinal cancers.

U.S. Pat. Nos. 6,670,396, 7,053,230, 7,709,669, 7,737,178, and 8,349,896describe aspirin triggered lipid mediators and their use in methods fortreating inflammation, for example where the inflammation manifests asCrohn's disease, ulcerative colitis, distal proctitis, rheumatoidspondylitis, arthritis, rheumatoid arthritis, osteoarthritis, goutyarthritis, psoriasis, dermatitis, eczematous dermatitis, atopic orseborrheic dermatitis, allergic or irritant contact dermatitis, eczemacraquelee, photoallergic dermatitis, phototoxic dermatitis,phytophotodermatitis, radiation dermatitis, stasis dermatitis, arterialinflammation, coronary infarct damage, restenosis, uveitis, iritis,conjunctivitis, adult respiratory distress syndrome, bronchitis, cysticfibrosis, a spasmogenic condition, asthma, idiopathic bronchial asthma,arterial smooth muscle constriction, coronary spasm, myocardialinfarction, ischemia-induced myocardial injury, cerebral spasm, stroke,inflammatory bowel disorder, spastic colon, mucous colitis, an allergiccondition, eczema, an allergic bowel disease, coeliac disease, anallergic eye condition, hay fever, allergic rhinitis, allergicconjunctivitis, a condition involving blood platelet aggregation,coronary thrombosis, phlebitis, or phlebothrombosis, and methods oftreating cardiovascular disease.

US 20120245229 describes methods of treating neuropathic pain, includingpain associated with diabetic neuropathy or HIV infection, methods oftreating post-operative pain, inflammatory pain, pain associated withcancer, and pain associated with fibromyalgia, by administeringresolvins.

Lim et al. describes the analgesic potency of SPMs in a large number ofinflammatory pain models and characterizes resolvins and relatedsubstances as therapeutic candidates for preventing deterioration ofinflammation and pathologic pain. See Lim et al. “Biological Roles ofResolvins and Related Substances in the Resolution of Pain” BioMedResearch International 2015, pp. 1-14, Article ID 830930. Lin also notesthat “the powerful potencies” and “negligible adverse effects” of thesemolecules make them attractive candidates agents for clinical use.

US 20150126602 describes oils with anti-inflammatory activity containingnatural specialized proresolving mediators and their precursors, such as18HEPE and 17HDHA, and methods of using same for treating aninflammatory condition such as cardiovascular disease (includingatherosclerosis, high blood pressure, hypercholesterolemia,hypertriglyceridemia, endothelial hyporeactivity, cardiac infarction andcerebral stroke), metabolic syndrome (e.g., characterized by loss ofinsulin sensitivity, obesity, hepatic steatosis and/or cholestasis),neurodegenerative disease (e.g., Alzheimer's disease, Parkinson disease,multiple sclerosis and apraxia), atopic/allergic reactions,osteoarthritis, rheumatoid arthritis, inflammatory pain, acne,psoriasis, rosacea, asthma, acute lung injury, chronic obstructivepulmonary disease, cystic fibrosis, sepsis, allergic rhinitis,sinusitis, periodontitis, inflammatory bowel disease, Crohn's disease,macular degeneration, dry eye syndrome, gastric ulceration, cancer, andauto-inflammatory disorders.

U.S. Pat. No. 7,378,444 and U.S. Pat. No. 7,595,341 describe analogs oflipid mediators derived from omega-3 fatty acids and methods of use fortreating inflammatory, angioproliferative, cardiovascular,thrombophlebotic, vascular, ocular, dermatologic, neurodegenerative,pulmonary, endocrine, reproductive, rheumatologic and gastrointestinaldiseases.

There is a need to develop compositions able to deliver SPMs and otherlipid mediators of inflammation, including their analogs andderivatives, in therapeutically effective amounts to target tissues inorder to fulfill the therapeutic promise of these compounds andtranslate the many promising in vitro and cellular pharmacologyobservations into clinical benefits. The present invention addressesthese needs.

SUMMARY OF THE INVENTION

The present invention provides new salt forms of specializedpro-resolving mediators (referred to herein as “SPMs”) which includelipoxins, resolvins, protectins, and their aspirin-triggeredcounterparts. The SPM salts described here contain at least one or twoSPM molecules ionically bound to at least one basic function that isprovided by a scaffold as described in Formulas I-IV. For example, incompounds of Formulas I and III, the scaffold is peptide-based; incompounds of Formula IV, the scaffold is a divalent metal-amino acidchelate or divalent metal-peptide chelate; and in compounds of FormulaII, the scaffold is either a dipeptide or a monovalent metal ornon-metal dipeptide.

The at least one or two SPM molecules forming the anionic counterioncomponent of the salts described here may be referred to as “the SPMcomponent” of the compounds and compositions described herein. Inembodiments, the SPM component comprises or consists of an SPM selectedfrom the group consisting of resolvin D1 (RvD1), resolvin D2 (RvD2),resolvin E1 (RvE1), protectin DX (PDX), and lipoxin A4 (LXA4). Inembodiments, the SPM component comprises or consists of an SPM selectedfrom an aspirin-triggered (AT) resolvin, lipoxin, or protectin. Inembodiments, the AT resolvin, lipoxin, or protectin is selected from thegroup consisting of AT-RvD1, AT-RvD2, AT-PD1, AT-LXA4, and AT-RvE1. Inembodiments, the SPM component is selected from the group consisting ofRvE1, LXA4, AT-LXA4, and AT-RvE1. In embodiments, the SPM componentconsists of RvE1 or LXA4. The chemical names and formulas of these SPMcompounds are provided for reference infra, in Tables 1-4.

Specific, non-limiting examples of the structures of some compounds ofFormulas I, III, and IV are shown in Table 5.

In embodiments, an SPM salt described here is stabilized againstchemical degradation compared to the free acid form of the SPM. Inembodiments, an SPM salt described here has improved bioavailabilitycompared to the free acid form of the SPM.

The compounds described here can be readily combined, e.g., by physicaladmixture, with each other and with other biologically active agents toproduce a solid dosage form, or dissolved in aqueous media to produce aliquid dosage form. The compounds described here are thus suitable forformulation as aqueous liquids, e.g., for parenteral forms ofadministration including via intravenous and intramuscular injection, inaddition to their suitability for formulation as solid dosage forms,such as oral or rectal dosage forms. These and other advantages aredescribed in more detail infra.

In embodiments, the compounds and compositions described here are usefulfor treating a disease or disorder characterized by excessiveinflammation.

In embodiments, the disease or disorder is an inflammatory bowel disease(IBD) related disease or disorder selected from ulcerative colitis,Crohn's disease, proctitis, pouchitis, Crohn's disease of the pouch,eosinophilic colitis, lymphocytic colitis, collagenous colitis,diversion colitis, chemical colitis, and ischemic colitis. Inembodiments, the IBD-related disease or disorder is ulcerative colitisor Crohn's disease. In embodiments, the IBD-related disease or disorderis pouchitis.

In embodiments, the disease or disorder is a gastrointestinal disease ordisorder selected from eosinophilic esophagitis, Behcet's disease,irritable bowel syndrome, Celiac disease, intestinal mucositis,diverticulitis, and short bowel syndrome. In embodiments, thegastrointestinal disease or disorder is intestinal mucositis.

In embodiments, the disease or disorder is a dermatological disease ordisorder selected from dermatitis, diabetic wound, eczema, pruritus,healing wound, acne, and steroid-induced rosacea. In embodiments, thedermatological disease or disorder is selected from dermatitis, eczema,pruritis, acne, and steroid-induced rosacea.

In embodiments, the disease or disorder is an inflammatory disease ordisorder selected from asthma, ischemia reperfusion injury, lymearthritis, periodontitis, peritonitis, psoriasis, rheumatoid arthritis,scleroderma, oral mucositis, stomatitis, chelitis, glossitis, Sjogren'ssyndrome and systemic inflammatory response syndrome. In embodiments,the inflammatory disease or disorder selected from asthma, psoriasis,scleroderma, and oral mucositis.

In embodiments, the disease or disorder is a neurological disease ordisorder selected from postoperative delirium, acute postsurgical pain,fibromyalgia, endometriosis, vulvodynia, chronic lower back pain,treatment or management of pain associated with osteoarthritis, diabeticperipheral neuropathy and musculoskeletal injury or trauma.

Compounds of Formula I

In embodiments, the disclosure provides compounds of Formula I or anenantiomer, polymorph, solvate, or hydrate thereof:

-   -   wherein    -   A and B are each independently an SPM molecule;    -   A and B may be the same or different;    -   either A or B, but not both, may be absent,    -   R¹ and R² are each independently a C₁-C₁₀ alkyl comprising at        least one basic function and is optionally branched;    -   X is H or CO—Z and Z is a single amino acid residue or a peptide        comprising 2 to 18 amino acid residues;    -   when either A or B is absent:        -   one of R¹, R² and CO—Z is protonated; or    -   X is H and is positively charged; and        -   the one of R¹, R² and the CO—Z that is protonated or the            positively charged H forms an ionic bond with either A or B;            and    -   when A and B are both present:        -   two of R¹, R² and CO—Z are protonated; or        -   one of R¹, R² and CO—Z is protonated, and X is H and is            positively charged; and        -   the two of R¹, R² and the CO—Z that are protonated or the            one of R¹, R² and the CO—Z that is protonated and the            positively charged H each respectively form an ionic bond            with A and B.

Compounds of Formula I comprise a peptide component consisting of atleast 2 amino acid moieties, and one or two SPM molecules (A, B) as theSPM component. In embodiments, A and B are the same and each isindependently selected from the group consisting of LXA4, AT-LXA4, PDX,RvE1, AT-RvE1, RvD1, AT-RvD1, RvD2 and AT-RvD2. The SPM component isdescribed in more detail below. 1251 The peptide component may be from 2to 10 or 2 to 20 amino acids in length, preferably 2, 3, 4, or 5 aminoacids in length. The peptide component consists of 2 amino acid residueswhen X is H, or is a peptide of from 3 to 5, 3 to 10, or 3 to 20 aminoacid residues where X is CO—Z.

In embodiments, X is H and the peptide component consists of a dipeptideof amino acids independently selected from lysine, arginine, andglutamine, or a derivative of one or more of the foregoing. Inembodiments, X is H and the peptide component consists of a dipeptide oflysine.

In embodiments, X is H and R¹ and R² are each independently selectedfrom —(CH₂)₃—NHC(NH₂ ⁺)—NH₂, —(CH₂)₄—NH₃ ⁺, and —(CH₂)₂—C(O)NH₃ ⁺. Inembodiments, R¹ and R² are the same. In embodiments, R¹ and R² aredifferent.

In embodiments, A and B are the same and selected from the groupconsisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2, AT-PD1,AT-LXA4, and AT-RvE1; R¹ and R² are both —(CH₂)₄—Y², Y² is NH₃ ⁺, and Xis H. This selection of R¹, R², and Y² may be referred to herein as a“lysyl lysine” (lys-lys) dipeptide. In this embodiment, the peptidecomponent is a lysine dipeptide.

In embodiments, the compound of Formula I is selected from a mono or bisRvE1 lysyl lysine. In an embodiment, the compound of Formula I is bisRvE1 lys-lys. In embodiments, the compound of Formula I is selected froma mono or bis AT-RvE1 lysyl lysine. In an embodiment, the compound ofFormula I is his AT-RvE1 lys-lys.

In embodiments, the compound of Formula I is selected from a mono or hisLXA4 lysyl lysine. In an embodiment, the compound of Formula I is bisLXA4 lys-lys. In embodiments, the compound of Formula I is selected froma mono or his AT-LXA4 lysyl lysine. In an embodiment, the compound ofFormula I is bis AT-LXA4 lys-lys.

In embodiments, the compound of Formula I is selected from a mono or hisRvD1 lysyl lysine. In embodiments, the compound of Formula I is selectedfrom a mono or bis AT-RvD1 lysyl lysine.

In embodiments, the compound of Formula I is selected from a mono or hisRvD2 lysyl lysine. In embodiments, the compound of Formula I is selectedfrom a mono or his AT-RvD2 lysyl lysine.

In embodiments, the compound of Formula I is selected from a mono or hisPDX lysyl lysine.

Exemplary compounds of the lys-lys embodiment of Formula I are providedin Table 5. In embodiments, the compound of Formula I is selected fromthe group consisting of Compounds 4, 9, 14, 19, 24, 29, 34, and 39 ofTable 5. In embodiments, the compound of Formula I is selected from thegroup consisting of Compounds 4, 9, 24, 29, 34, and 39 of Table 5. Inembodiments, the compound of Formula I is selected from the groupconsisting of Compounds 4 and 9 of Table 5.

In embodiments, a Compound of Formula I, or a composition comprisingsame, is used in a method for treating a disease or disordercharacterized by excessive inflammation. In embodiments, the disease ordisorder is disorder is an IBD-related disease or disorder selected fromulcerative colitis, Crohn's disease, proctitis, pouchitis, Crohn'sdisease of the pouch, eosinophilic colitis, lymphocytic colitis,collagenous colitis, diversion colitis, chemical colitis, and ischemiccolitis. In embodiments, the IBD-related disease or disorder isulcerative colitis or Crohn's disease. In embodiments, the IBD-relateddisease or disorder is pouchitis.

In embodiments, the disclosure provides a method for treating anIBD-related disease or disorder as described above, the methodcomprising administering to a subject in need of such treatment, aCompound of Formula I. In embodiments of the methods, the Compound ofFormula I is selected from a mono or his RvE1 lysyl lysine, a mono orbis AT-RvE1 lysyl lysine, a mono or bis LXA4 lysyl lysine, and a mono orbis AT-LXA4 lysyl lysine.

Compounds of Formula II

In embodiments, the disclosure provides compounds of Formula II or anenantiomer, polymorph, solvate, or hydrate thereof:

where R¹ is H, or absent. X¹ and X² are each independently the sidechain of an amino acid residue. M is a positively charged optionalmolecule. B is an SPM molecule.

A compound of Formula II consists of at least (i) a dipeptide componentand (ii) an SPM component (B), with a positively charged optionalmolecule (M). The dipeptide component contains X¹ and X² which may bethe same or different, and are each the side chain of an amino acidresidue. In embodiments, at least one of X¹ and X² is the side chain ofan amino acid residue selected from serine, threonine, glycine, alanine,valine, leucine, isoleucine, methionine, and phenylalanine. Inembodiments, where one of X¹ and X² is the side chain of an amino acidresidue selected from serine, threonine, glycine, alanine, valine,leucine, isoleucine, methionine, and phenylalanine, the remainder of X¹or X² is the side chain of an amino acid independently selected fromlysine, arginine, histidine, aspartate, glutamate, serine, threonine,asparagine, glutamine, cysteine, glycine, proline, alanine, valine,isoleucine, leucine, methionine, phenylalanine, tyrosine, andtryptophan. In embodiments, the remainder is the side chain of lysine.In embodiments, at least one of X¹ and X² is the side chain of glycine,valine, serine, leucine, or histidine, and the remainder is the sidechain of lysine.

The positively charged optional molecule (M) has at least one basicfunction in protonated form which forms an ionic bond with the terminalcarboxyl of the amino acid component. In embodiments, M is a monovalentmetal cation, e.g., Na⁺, K⁺, or a molecule having at least one basicfunction, such as a monovalent amine-based cation, e.g.,tri-ethanolamine, or tri-ethylamine, or a basic pharmaceutical compoundsuch as metformin or gabapentin.

As described in more detail below, the compounds of Formula II encompasssimple salts of dipeptides and an SPM (Formula IIa), simple metal saltsof the dipeptides and an SPM with a monovalent metal (Formula lib), andsimple non-metal salts of the dipeptides and an SPM with a non-metalmolecule having at least one basic function (Formula IIc).

In embodiments of the compound of Formula II, B is selected from thegroup consisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2,AT-LXA4, and AT-RvE1.

In embodiments, the compound of Formula II is a glycine dipeptide whereR¹ is H, X¹ and X² are each H, M is absent and B is selected from thegroup consisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2,AT-LXA4, and AT-RvE1.

In embodiments, the disclosure provides a method for treating a diseaseor disorder selected from an IBD-related disease or disorder asdescribed above, the method comprising administering to a subject inneed of such treatment, a Compound of Formula II.

Compounds of Formula III

In embodiments, the disclosure provides compounds of Formula III or anenantiomer, polymorph, solvate, or hydrate thereof:

-   -   wherein    -   R² is a C₁-C₁₀ alkyl comprising at least one basic function;    -   A and B are each independently an SPM molecule;    -   A and B may be the same or different; and    -   either A or B, but not both, may be absent.

In embodiments, R² is the side chain of an amino acid residue selectedfrom lysine, arginine, and glutamine. In embodiments, R² is selectedfrom the group consisting of —(CH₂)₃—NHC(NH₂ ⁺)NH₂, —(CH₂)₄—NH₃ ⁺, and—(CH₂)₂—C(O)NH₃ ⁺. In embodiments, R² is —(CH₂)₄—NH₃ ⁺.

In an embodiment of the compound of Formula III, A and B are the sameand selected from the group consisting of RvD1, RvD2, RvE1, PDX, LXA4,AT-RvD1, AT-RvD2, AT-PD1, AT-LXA4, and AT-RvE1, and R² is —(CH₂)₄—NH₃ ⁺.This selection of R² may be referred to herein as a “linear lysyllysine” (linear lys-lys) dipeptide. In this embodiment, the peptidecomponent is a lysine dipeptide.

In embodiments, the compound of Formula III is selected from a mono orhis RvE1 linear lysyl lysine. In an embodiment, the compound of FormulaIII is bis RvE1 linear lys-lys. In embodiments, the compound of FormulaIII is selected from a mono or bis AT-RvE1 linear lysyl lysine. In anembodiment, the compound of Formula III is bis AT-RvE1 linear lys-lys.

In embodiments, the compound of Formula III is selected from a mono orbis LXA4 linear lysyl lysine. In an embodiment, the compound of FormulaIII is bis LXA4 linear lys-lys. In embodiments, the compound of FormulaIII is selected from a mono or bis AT-LXA4 lysyl lysine. In anembodiment, the compound of Formula III is bis AT-LXA4 linear lys-lys.

In embodiments, the compound of Formula III is selected from a mono orhis RvD1 linear lysyl lysine. In embodiments, the compound of FormulaIII is selected from a mono or his AT-RvD1 linear lysyl lysine.

In embodiments, the compound of Formula III is selected from a mono orhis RvD2 linear lysyl lysine. In embodiments, the compound of FormulaIII is selected from a mono or bis AT-RvD2 linear lysyl lysine.

In embodiments, the compound of Formula III is selected from a mono orbis PDX linear lysyl lysine.

Exemplary compounds of Formula III are provided in Table 5. Inembodiments, a compound of Formula III is selected from the groupconsisting of Compounds 5, 10, 15, 20, 25, 30, 35, and 40 of Table 5. Inembodiments, a compound of Formula III is selected from the groupconsisting of Compounds 5 and 10 (RvE1 and AT-RvE1 embodiments) of Table5. In embodiments, a compound of Formula III is selected from the groupconsisting of Compounds 15 and 20 (LXA4 and AT-LXA4 embodiments) ofTable 5.

In embodiments, a Compound of Formula III, or a composition comprisingsame, is used in a method for treating a disease or disordercharacterized by excessive inflammation. In embodiments, the disease ordisorder is disorder is an IBD-related disease or disorder selected fromulcerative colitis, Crohn's disease, proctitis, pouchitis, Crohn'sdisease of the pouch, eosinophilic colitis, lymphocytic colitis,collagenous colitis, diversion colitis, chemical colitis, and ischemiccolitis. In embodiments, the IBD-related disease or disorder isulcerative colitis or Crohn's disease. In embodiments, the IBD-relateddisease or disorder is pouchitis.

In embodiments, the disclosure provides a method for treating anIBD-related disease or disorder as described above, the methodcomprising administering to a subject in need of such treatment, aCompound of Formula III. In embodiments, the Compound of Formula III foruse in the method is selected from a mono or bis RvE1 linear lysyllysine, a mono or bis At-RvE1 linear lysyl lysine, a mono or bis LXA4linear lysyl lysine, and a mono or bis AT-LXA4 linear lysyl lysine.

Compounds of Formula IV

In embodiments, the disclosure provides compounds of Formula IV or anenantiomer, polymorph, solvate, or hydrate thereof:

-   -   wherein    -   M is a divalent metal;    -   A and B are each independently a fatty acid anion;    -   A and B may be the same or different;    -   either A or B, but not both, may be absent;    -   R¹ and R² are each independently a C₁-C₁₀ alkyl comprising at        least one basic function;    -   X¹ and X² are each independently H or CO—Z and Z is a peptide        comprising 1 to 5 amino acids or a pharmaceutically acceptable        salt thereof;    -   when either A or B is absent:        -   one of R¹, R² and the two CO—Z's is protonated; or        -   one of the two H's is positively charged; and        -   the one of R¹, R² and the two CO—Z's that is protonated or            the one of the positively charged H's forms an ionic bond            with either A or B; and    -   when A and B are both present:        -   two of R¹, R² and the two CO—Z's are protonated; or        -   one of R¹, R² and the two CO—Z's is protonated, and one of            the two H's is positively charged; and        -   the two of R¹, R² and the two CO—Z's that are protonated or            the one of R¹, R² and the two CO—Z's that is protonated and            the positively charged H each respectively form an ionic            bond with A and B.

Compounds of Formula IV have two amino acid moieties coordinated arounda divalent metal cation as the amino acid component and one or two SPMmolecules as the SPM component. In embodiments, the divalent metal isMg²⁺, Ca²⁺, Mn²⁺, Fe²⁺, Cu²⁺, Co²⁺, Ni²⁺, Mo²⁺ or Zn²⁺. In embodiments,the divalent metal is Mg²⁺. In embodiments, the divalent metal is Ca²⁺.In embodiments, the divalent metal is Zn²⁺. In embodiments, the aminoacid component includes or consists of lysine or arginine. Inembodiments, the amino acid component includes lysine or arginine. Inembodiments, the basic function of R¹ and R² is selected from a primaryamine, a secondary amine, a tertiary amine, and a guanidine. Inembodiments, basic function refers to —NH₃, —NHC(NH₂ ⁺)—NH₂, —NHR⁶R⁷, or—NR⁶R⁷R⁸, wherein R⁶, R⁷, R⁸ are each independently hydrogen, —CN,—COOH, —CONH₂, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl; R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a unsubstitutedheterocycloalkyl or unsubstituted heteroaryl. In embodiments, the basicfunction is a hydrogen bond acceptor. In embodiments, the basic functionis a hydrogen bond donor. In embodiments, the basic function is apositively charged amine.

In embodiments, R¹ and R² are each the side chain of an amino acidresidue having a basic function. In embodiments, R¹ and R² are the sameand the amino acid residue is lysine or arginine.

In embodiments, R¹ and R² are independently selected from —(CH₂)₃—Y¹,and —(CH₂)₄—Y², where Y¹ and Y² are each a basic function which may bethe same or different. In embodiments, R¹ is —CH₂CH₂NH₃. In embodiments,R² is —CH₂CH₂NH₃. In embodiments, R¹ is —CH₂CH₂CH₂CH₂NH₃. Inembodiments, R² is —CH₂CH₂CH₂CH₂NH₃.

In embodiments, R¹ and R² are both —(CH₂)₄—Y², and Y² is —NH₃₊.

In embodiments, R¹ and R² are both —(CH₂)₃—Y¹, and Y¹ is —NHC(NH₂ ⁺)NH₂.

In embodiments, R¹ is —(CH₂)₃—Y¹, Y¹ is —NHC(NH₂ ⁺)NH₂, R² is—(CH₂)₄—Y², and Y² is NH₃ ⁺. In embodiments, R¹ is —(CH₂)₄—Y², Y² is NH₃⁺, R² is —(CH₂)₃—Y¹, and Y¹ is NHC(NH₂ ⁺)NH₂.

In embodiments, X¹ and X² are the same and are hydrogen (H).

In embodiments, the SPM molecule of A and B is as described infra.

In an embodiment of the compound of Formula IV, A and B are the same andselected from the group consisting of RvD1, RvD2, RvE1, PDX, LXA4,AT-RvD1, AT-RvD2, AT-PD1, AT-LXA4, and AT-RvE1; M is Mg²⁺, Ca²⁺, orZn²⁺, R¹ and R² are both —(CH₂)₄—Y² and Y² is NH₃ ⁺; and X¹ and X² areH. This selection of R¹, R², and Y² may be referred to herein as themetal “di-lysinate”, e.g., “magnesium di-lysinate” or “Mg-di-lysinate”.In this embodiment, the peptide component consists of a lysinedipeptide.

In embodiments, the compound of Formula IV is selected from a mono orbis RvE1 Mg-di-lysinate. In an embodiment, the compound of Formula IV ishis RvE1 Mg-di-lysinate. In embodiments, the compound of Formula IV isselected from a mono or his AT-RvE1 Mg-di-lysinate. In an embodiment,the compound of Formula IV is bis AT-RvE1 Mg-di-lysinate.

In embodiments, the compound of Formula IV is selected from a mono orhis LXA4 Mg-di-lysinate. In an embodiment, the compound of Formula IV isbis LXA4 Mg-di-lysinate. In embodiments, the compound of Formula IV isselected from a mono or bis AT-LXA4 Mg-di-lysinate. In an embodiment,the compound of Formula IV is bis AT-LXA4 Mg-di-lysinate.

In embodiments, the compound of Formula IV is selected from a mono orbis RvD1 Mg-di-lysinate. In embodiments, the compound of Formula IV isselected from a mono or bis AT-RvD1 Mg-di-lysinate.

In embodiments, the compound of Formula IV is selected from a mono orhis RvD2 Mg-di-lysinate. In embodiments, the compound of Formula IV isselected from a mono or his AT-RvD2 Mg-di-lysinate.

In embodiments, the compound of Formula IV is selected from a mono orhis PDX Mg-di-lysinate.

Exemplary compounds of Formula IV are provided in Table 5. Inembodiments, a compound of Formula IV is selected from the groupconsisting of Compounds 1-3, 6-8, 11-13, 16-18, 21-23, 26-28, 31-33, and36-38 of Table 5. In embodiments, a compound of Formula IV is selectedfrom the group consisting of Compounds 1-3 and 6-8 of Table 5 (RvE1 andAT-RvE1 embodiments). In embodiments, a compound of Formula IV isselected from the group consisting of Compounds 11-13 and 16-18 of Table5 (LXA4 and AT-LXA4 embodiments). In embodiments, a compound of FormulaIV is selected from the group consisting of Compounds 21-23 and 26-28 ofTable 5 (RvD1 and AT-RvD1 embodiments).

In embodiments, a Compound of Formula IV, or a composition comprisingsame, is used in a method for treating a disease or disordercharacterized by excessive inflammation. In embodiments, the disease ordisorder is disorder is an IBD-related disease or disorder selected fromulcerative colitis, Crohn's disease, proctitis, pouchitis, Crohn'sdisease of the pouch, eosinophilic colitis, lymphocytic colitis,collagenous colitis, diversion colitis, chemical colitis, and ischemiccolitis. In embodiments, the IBD-related disease or disorder isulcerative colitis or Crohn's disease. In embodiments, the IBD-relateddisease or disorder is pouchitis.

In embodiments, the disclosure provides a method for treating a diseaseor disorder selected from an IBD-related disease or disorder asdescribed above, the method comprising administering to a subject inneed of such treatment, a Compound of Formula IV. In embodiments, theCompound of Formula IV is selected from a mono or bis RvE1 Mg, Ca, or Zndi-lysinate, a mono or bis AT-RvE1 Mg, Ca, or Zn di-lysinate, a mono orbis LXA4 Mg, Ca, or Zn di-lysinate, and a mono or bis AT-LXA4 Mg, Ca, orZn di-lysinate. In embodiments, the di-lysinate is a magnesiumdi-lysinate.

The SPM Component

As discussed above, the compounds represented by Formulas I-IV eachcontain at least one or two SPM molecules, which may be referred toherein as the “SPM component” of the compound, and a scaffold portion towhich the SPM component is ionically bound. The terms “mono” and “bis”refer to one (mono) or two (bis) SPM molecules in the salt compound.

The term “SPM” refers to SPMs such as protectins and resolvins as wellas to lipoxins and aspirin-triggered lipid mediators (e.g.,aspirin-triggered lipoxins and protectins), as described in more detailinfra. Examples of particular SPM molecules that may form the SPMcomponent of the compounds described here, as well as their precursormolecules, are given in Tables 1-4 infra. It is understood that theneutral compounds described in these tables may become charged (i.e.,deprotonated) if solvated at the appropriate pH.

In embodiments, the SPM component of a compound described here comprisesor consists of one or two SPM molecules selected from mediators derivedfrom arachidonic acid (AA) (Table 1), mediators derived fromeicosapentaenoic acid (EPA) (Table 2); mediators derived fromdocosahexaenoic acid (DHA) (Table 3); and aspirin-triggered mediators(Table 4). In embodiments, the SPM component of a compound describedhere comprises or consists of two SPM molecules selected from Tables1-4. In embodiments, the two SPM molecules are the same or different. Inembodiments, the two SPM molecules are the same and are selected fromthe group consisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2,AT-PD1, AT-LXA4, and AT-RvE1. In embodiments, the SPM component of acompound described here consists of one or two SPM molecules selectedfrom the group consisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1,AT-RvD2, AT-PD1, AT-LXA4, and AT-RvE1. In embodiments, the SPM componentis selected from RvE1, AT-RvE1, LXA4, and AT-LXA4.

The present disclosure also provides compositions including a singlecompound described herein, or compositions comprising mixtures of two ormore different compounds described herein. In embodiments, thecomposition is a pharmaceutical or veterinary composition and thecarrier is acceptable for administration to humans or animals.

In embodiments, the composition is a pharmaceutical composition in theform of a solid oral dosage form, a dosage form suitable for rectaladministration, or a parenteral dosage form. In embodiments, the dosageform suitable for rectal administration is an ointment, suppository, orenema. In embodiments, the parenteral dosage form is suitable forintravenous, intra-arterial, or intramuscular administration, e.g., viainjection of an aqueous liquid.

The present disclosure also provides methods of use for the compoundsdescribed here, and for the compositions comprising same. Inembodiments, a compound described here, or a composition comprisingsame, is useful for treating a disease or disorder in which resolutionof inflammation provides a beneficial effect, such as thosecharacterized by chronic or excessive inflammation. For example, thecompounds and compositions described here are useful in treatinggastrointestinal diseases and disorders, pulmonary diseases anddisorders, arthritic diseases and disorders, cardiovascular diseases anddisorders, metabolic diseases and disorders, infectious diseases anddisorders, and neurological diseases and disorders.

In embodiments, the disclosure provides methods of treating agastrointestinal (GI) disease or disorder by administering to a subjectin need of such treatment a Compound of Formula I, II, III, or IV,wherein the GI disease or disorder is selected from those describedinfra in the section entitled “Pharmaceutical Uses”. In embodiments ofthe methods, the compound is a Compound of Formula I having alysyl-lysine dipeptide component and an SPM component selected from thegroup consisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2,AT-LXA4, and AT-RvE1. In embodiments, the SPM component is selected fromRvE1, AT-RvE1, LXA4, and AT-LXA4. In embodiments of the methods, thecompound is a Compound of Formula IV having a magnesium, calcium, orzinc di-lysinate peptide component and an SPM component selected fromthe group consisting of RvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2,AT-LXA4, and AT-RvE1. In embodiments, the SPM component is selected fromRvE1, AT-RvE1, LXA4, and AT-LXA4. The SPM component may be mono or bis,but is preferably bis.

The present disclosure also provides a package or kit comprising a unitdosage form of a compound described herein, or a composition comprisingsame, at least one container for holding the unit dosage forms, andinstructions for use.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A,B: Chemical Stability of RvE1. A, HPLC trace of RvE1 free acidat time zero. B, HPLC trace of RvE1 at 8-weeks.

FIG. 2A,B: Chemical Stability of RvE1 Mg-di-lysinate. A, HPLC trace ofRvE1 Mg-di-lysinate at time zero. B, HPLC trace of RvE1 Mg-di-lysinateat 8 weeks.

FIG. 3A,B: Chemical Stability of RvE1 Ca-di-lysinate. A, HPLC trace ofRvE1 Ca-di-lysinate at time zero. B, HPLC trace of RvE1 Ca-di-lysinateat 6 weeks.

FIG. 4A,B: Chemical Stability of RvE1 lysyl lysine. A, HPLC trace ofRvE1 lysyl lysine at time zero. B, HPLC trace of RvE1 lysyl lysine at8-weeks.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new salt forms of specializedpro-resolving mediators (referred to herein as “SPMs”) which includelipoxins, resolvins, protectins, and their aspirin-triggeredcounterparts, as described in more detail infra. The compounds describedhere advantageously provide SPM molecules in a pharmacologically usefulform due at least in part to their increased physical and/or chemicalstability.

The compounds described here contain at least one or two SPM moleculesionically bound to at least one basic function that is provided by ascaffold as described in Formulas I-IV below. In general, the carboxylicacid moiety of the SPM molecule or molecules forming the SPM componentof the compounds described here is deprotonated to form an ionic bondwith a basic function (or functions) of the scaffold portion of thecompound.

The compounds described herein can exist in unsolvated forms as well assolvated forms, including hydrated forms. In general, the solvated formsare equivalent to unsolvated forms and are intended to be encompassedwithin the scope of the present invention. In general, all physicalforms are equivalent for the uses contemplated by the present inventionand are intended to be within the scope of the present invention.

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts. For example, in instances where asubstituents such as —NH₃ are shown without a charge, it is understoodto possess a formal charge, i.e. NH₃ ⁺.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons).

The term “basic function” refers to a positively charged or protonatedprimary amine, a positively charged secondary amine, a positivelycharged tertiary amine, or a positively charged guanidine. Inembodiments, basic function refers to —NH₃ ⁺, —NHC(NH₂ ⁺)NH₂, —NHR⁶R⁷,—NR⁶R⁷R⁸, wherein R⁶, R⁷, and R⁸ are each independently hydrogen, —CN,—COOH, —CONH₂, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl; R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a unsubstitutedheterocycloalkyl or unsubstituted heteroaryl. In embodiments, the basicfunction is a hydrogen bond acceptor. In embodiments, the basic functionis a positively charged amine.

It is understood that due to resonance a charge may be distributedacross the molecule. The chemical structures and formulae set forthherein are constructed according to the standard rules of chemicalvalency known in the chemical arts, and as such one of skill in the artwould recognize the equivalency of the moieties possessing resonancestructures. For example, —NHC(NH₂ ⁺)NH₂ refers to

In embodiments, the “side chain of an amino acid” or “side chain” or“side-chain” as used herein is used in accordance with its ordinarymeaning and refers to the functional substituent contained on naturallyoccurring amino acids. Naturally occurring amino acids are those encodedby the genetic code (e.g. alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, or valine), as well as those amino acids that arelater modified, e.g., hydroxyproline, γ-carboxyglutamate, andO-phosphoserine. In embodiments, the side chain of an amino acid isionized (e.g., it has a formal charge).

In embodiments, the side chain is selected from the group consisting ofH,

In embodiments, the side chain is H. In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain may optionally be joined to an adjacentnitrogen to form a unsubstituted heterocycloalkyl (e.g., pyrolidinyl).

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

In embodiments, the side chain is

The side chain of glycine is H. The side chain of arginine is

The side chain of arginine is

The side chain of histidine is

The side chain of lysine is

The side chain of aspartic acid is

The side chain of glutamic acid is

The side chain of serine is

The side chain of threonine is

The side chain of asparagine is

The side chain of glutamine is

The side chain of cysteine is

The side chain of proline is

The side chain of alanine is

The side chain of valine is

The side chain of isoleucine is

The side chain of leucine is

The side chain of methionine is

The side chain of phenylalanine is

The side chain of tyrosine is

The side chain of tryptophan is

The term “non-natural amino acid side-chain” refers to the functionalsubstituent of compounds that have the same basic chemical structure asa naturally occurring amino acid, i.e., an a carbon that is bound to ahydrogen, a carboxyl group, an amino group, and an R group, e.g.,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, allylalanine, 2-aminoisobutryric acid. Non-natural aminoacids are non-proteinogenic amino acids that either occur naturally orare chemically synthesized. Such analogs have modified R groups (e.g.,norleucine) or modified peptide backbones, but retain the same basicchemical structure as a naturally occurring amino acid. Non-limitingexamples include exo-cis-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxylicacid hydrochloride, cis-2-Aminocycloheptanecarboxylic acidhydrochloride, cis-6-Amino-3-cyclohexene-1-carboxylic acidhydrochloride, cis-2-Amino-2-methylcyclohexanecarboxylic acidhydrochloride, cis-2-Amino-2-methylcyclopentanecarboxylic acidhydrochloride, 2-(Boc-aminomethyl)benzoic acid, 2-(Boc-amino)octanedioicacid, Boc-4,5-dehydro-Leu-OH (dicyclohexylammonium),Boc-4-(Fmoc-amino)-L-phenylalanine, Boc-β-Homopyr-OH,Boc-(2-indanyl)-Gly-OH, 4-Boc-3-morpholineacetic acid,4-Boc-3-morpholineacetic acid, Boc-pentafluoro-D-phenylalanine,Boc-pentafluoro-L-phenylalanine, Boc-Phe(2-Br)—OH, Boc-Phe(4-Br)—OH,Boc-D-Phe(4-Br)—OH, Boc-D-Phe(3-Cl)—OH, Boc-Phe(4-NH2)-OH,Boc-Phe(3-NO2)-OH, Boc-Phe(3,5-F2)-OH,2-(4-Boc-piperazino)-2-(3,4-dimethoxyphenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(2-fluorophenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(3-fluorophenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(4-fluorophenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(4-methoxyphenyl)acetic acid purum,2-(4-Boc-piperazino)-2-phenylacetic acid purum,2-(4-Boc-piperazino)-2-(3-pyridyl)acetic acid purum,2-(4-Boc-piperazino)-2-[4-(trifluoromethyl)phenyl]acetic acid purum,Boc-β-(2-quinolyl)-Ala-OH, N-Boc-1,2,3,6-tetrahydro-2-pyridinecarboxylicacid, Boc-β-(4-thiazolyl)-Ala-OH, Boc-β-(2-thienyl)-D-Ala-OH,Fmoc-N-(4-Boc-aminobutyl)-Gly-OH, Fmoc-N-(2-Boc-aminoethyl)-Gly-OH,Fmoc-N-(2,4-dimethoxybenzyl)-Gly-OH, Fmoc-(2-indanyl)-Gly-OH,Fmoc-pentafluoro-L-phenylalanine, Fmoc-Pen(Trt)-OH, Fmoc-Phe(2-Br)—OH,Fmoc-Phe(4-Br)—OH, Fmoc-Phe(3,5-F2)-OH, Fmoc-β-(4-thiazolyl)-Ala-OH,Fmoc-β-(2-thienyl)-Ala-OH, 4-(Hydroxymethyl)-D-phenylalanine.

Formula I Compounds

In embodiments, the disclosure provides compounds of Formula I,including enantiomers, polymorphs, solvates, and hydrates thereof:

-   -   wherein    -   A and B are each independently an SPM molecule;    -   A and B may be the same or different;    -   either A or B, but not both, may be absent,    -   R¹ and R² are each independently a C₁-C₁₀ alkyl comprising at        least one basic function;    -   X is H or CO—Z and Z is a single amino acid residue or a peptide        comprising 2 to 18 amino acid residues;    -   when either A or B is absent:        -   one of R¹, R² and CO—Z is protonated; or    -   H is positively charged; and        -   the one of R¹, R² and the CO—Z that is protonated or the            positively charged H forms an ionic bond with either A or B;            and    -   when A and B are both present:        -   two of R¹, R² and CO—Z are protonated; or        -   one of R¹, R² and CO—Z is protonated, and H is positively            charged; and        -   the two of R¹, R² and the CO—Z that are protonated or the            one of R¹, R² and the CO—Z that is protonated and the            positively charged H each respectively form an ionic bond            with A and B.

Compounds of Formula I comprise a peptide component consisting of atleast 2 amino acid moieties, and one or two SPM molecules (A, B) as theSPM component. The SPM component is described in more detail below. Inembodiments, the SPM component comprises or consists of an SPM selectedfrom the group consisting of RvD1, RvD2, RvE1, PDX, and LXA4. Inembodiments, the SPM component comprises or consists of an SPM selectedfrom an aspirin-triggered (AT) resolvin, lipoxin, or protectin. Inembodiments, the AT resolvin, lipoxin, or protectin is selected from thegroup consisting of AT-RvE1, AT-RvD1, AT-RvD2, AT-PD1 and AT-LXA4. Inembodiments, the SPM component consists of RvE1, AT-RvE1, LXA4, orAT-LXA4. In embodiments, the SPM component consists of RvE1 or LXA4.

The peptide component may be from 2 to 10 or 2 to 20 amino acids inlength, preferably 2, 3, 4, or 5 amino acids in length. The peptidecomponent consists of 2 amino acid residues when X is H, or is a peptideof from 3 to 5, 3 to 10, or 3 to 20 amino acid residues where X is CO—Z.

Each amino acid moiety of the peptide component may, independently,comprise or consist of a single natural or non-naturally occurring aminoacid residue. In embodiments, the amino acid residues are independentlyselected from a residue of glycine, alanine, valine, leucine,isoleucine, serine, cysteine, threonine, methionine, proline,phenylalanine, tyrosine, tryptophan, histidine, lysine, arginine,aspartic acid, glutamic acid, asparagine, and glutamine.

R¹ and R² are each independently unsubstituted C₁-C₁₀ alkyl including atleast one basic function. In embodiments, the basic function is the sidechain of an amino acid moiety. In embodiments, the amino acid moiety isselected from lysine, arginine, and glutamine. In embodiments, the basicfunction is selected from the group consisting of a positively chargedprimary amine, a positively charged secondary amine, a positivelycharged tertiary amine, and a positively charged guanidine.

In embodiments, basic function refers to —NH₃—NHC(NH₂ ⁺)NH₂, —NHR⁶R⁷, or—NR⁶R⁷R⁸, wherein R⁶, R⁷, R⁸ are each independently hydrogen, —CN,—COOH, —CONH₂, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl; R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a unsubstitutedheterocycloalkyl or unsubstituted heteroaryl. In embodiments, the basicfunction is a positively charged amine. In embodiments, the basicfunction is a primary amine. In embodiments, the basic function is —NH₃⁺.

In embodiments, X is H and the peptide component consists of a dipeptideof amino acids independently selected from lysine, arginine, andglutamine, or a derivative of one or more of the foregoing.

In embodiments, X is CO—Z, and Z is either a single amino acid residueor a peptide of from 2 to 10 or 2 to 5 amino acid residues, and thepeptide component comprises at least one or two amino acidsindependently selected from lysine, arginine, and glutamine.

In embodiments, X is H and R¹ and R² are each independently selectedfrom —(CH₂)₃—NHC(NH₂ ⁺)NH₂, —(CH₂)₄—NH₃ ⁺, and —(CH₂)—C(O)NH₃ ⁺. Inembodiments, R¹ and R² are the same. In embodiments, R¹ and R² aredifferent.

In embodiments, X is CO—Z, and Z is either a single amino acid residueor a peptide of from 2 to 10 or 2 to 5 amino acid residues, and R¹ andR² are each independently selected from —(CH₂)₃—NHC(NH₂ ⁺)NH₂,—(CH₂)₄—NH₃ ⁺, and —(CH₂)₂—C(O)NH₃ ⁺. In embodiments, R¹ and R² are thesame. In embodiments, R¹ and R² are different.

In embodiments, —NHC(NH₂ ⁺)NH₂ is

In embodiments, either A or B is absent. Where either A or B is absent,the compound may be referred to as “mono” salt. In embodiments, A and Bare both present. Where A and B are both present, the compound may bereferred to as a “bis” salt. In one embodiment, A and B are each an SPM,and A and B are the same or different.

In embodiments, A and B are the same and selected from the groupconsisting of lipoxin A4, protectin DX, resolvin E1, resolvin D2, andaspirin triggered resolvin D1.

In embodiments, the compound of Formula I is a mono or bis SPMlysyl-lysine (lys-lys) compound selected from the group consisting ofLXA4 lys-lys, AT-LXA4 lys-lys, RvD1 lys-lys. AT-RvD1 lys-lys, RvE1lys-lys, AT-RvE1 lys-lys, PDX lys-lys, RvD2 lys-lys and AT-RvD2 lys-lys.In embodiments, the compound of Formula I is a mono or his SPM lys-lyscompound selected from the group consisting of AT-RvD1 lys-lys, AT-RvD2lys-lys, and AT-LXA4 lys-lys. In embodiments, the compound of Formula Iis selected from mono or bis RvE1 lys-lys and mono or bis AT-RvE1lys-lys. In embodiments, the compound of Formula I selected from mono orbis LXA4 lys-lys and mono or bis AT-LXA4 lys-lys.

Exemplary compounds of the lysyl-lysine embodiment of Formula I areprovided in Table 5. In embodiments, a compound of Formula I is selectedfrom the group consisting of Compounds 4, 9, 14, 19, 24, 29, 34, and 39of Table 5. In embodiments, a compound of Formula I is selected from thegroup consisting of Compounds 4, 9, 24, 29, 34, and 39 of Table 5. Inembodiments, a compound of Formula I is selected from the groupconsisting of Compounds 4 and 9 (RvE1 and AT-RvE1 embodiments). Inembodiments, a compound of Formula I is selected from the groupconsisting of Compounds 14 and 19 (LXA4 and AT-LXA4 embodiments).

In embodiments, a compound of Formula I is a lysyl-glutamine compoundselected from the group consisting of Lysyl-glutamine mono or bislipoxin A4 (LXA4), Lysyl-glutamine mono or bis aspirin triggeredresolvin D1 (AT-RvD1), Lysyl-glutamine mono or his resolvin E1 (RvE1),Lysyl-glutamine mono or his protectin DX (PDX), and Lysyl-glutamine monoor his resolvin D2 (RvD2).

Formula II Compounds

In embodiments, the disclosure provides compounds of Formula II or anenantiomer, polymorph, solvate, or hydrate thereof:

wherein R¹ is H, or absent, X¹ and X² are each independently the sidechain of an amino acid residue. M is a positively charged optionalmolecule, and B is an SPM molecule.

In embodiments, R¹ is H and X¹ and X² are the side chain of glycine.

In embodiments, R¹ is H and X¹ is the side chain of lysine, and X² isselected from the side chain of valine, the side chain of serine, theside chain of leucine, the side chain of histidine

A compound of Formula II consists of at least (i) a dipeptide componentand (ii) an SPM component (B), with a positively charged optionalmolecule (M). The dipeptide component contains X¹ and X² which may bethe same or different, and are each the side chain of an amino acidresidue. In embodiments, at least one of X¹ and X² is the side chain ofan amino acid residue selected from serine, threonine, glycine, alanine,valine, leucine, isoleucine, methionine, and phenylalanine. Inembodiments, where one of X¹ and X² is the side chain of an amino acidresidue selected from serine, threonine, glycine, alanine, valine,leucine, isoleucine, methionine, and phenylalanine, the remainder of X¹or X² is the side chain of an amino acid independently selected fromlysine, arginine, histidine, aspartate, glutamate, serine, threonine,asparagine, glutamine, cysteine, glycine, proline, alanine, valine,isoleucine, leucine, methionine, phenylalanine, tyrosine, andtryptophan. In embodiments, the remainder is the side chain of lysine.In embodiments, at least one of X¹ and X² is the side chain of glycine,valine, serine, leucine, or histidine, and the remainder is the sidechain of lysine.

In embodiments, the SPM component (B) comprises or consists of an SPMselected from the group consisting of RvD1, RvD2, RvE1, PDX, and LXA4.In embodiments, the SPM component comprises or consists of an SPMselected from an aspirin-triggered (AT) resolvin, lipoxin, or protectin.In embodiments, the AT resolvin, lipoxin, or protectin is selected fromthe group consisting of AT-RvE1, AT-RvD1, AT-RvD2, AT-PD1, and AT-LXA4.In embodiments, the SPM component consists of RvE1, AT-RvE1, LXA4, orAT-LXA4. In embodiments, the SPM component consists of RvE1 or LXA4.

The positively charged optional molecule (M) has at least one basicfunction which forms an ionic bond with the terminal carboxyl of theamino acid component. In embodiments, M is a monovalent metal cation,e.g., Na⁺, K⁺, or a molecule having at least one basic function, such asa monovalent amine-based cation, e.g., tri-ethanolamine, ortri-ethylamine, or a basic pharmaceutical compound such as metformin orgabapentin.

As described in more detail below, the compounds of Formula II encompasssimple salts of dipeptides and an SPM (Formula IIa), simple metal saltsof the dipeptides and an SPM with a monovalent metal (Formula IIb), andsimple non-metal salts of the dipeptides and an SPM with a non-metalmolecule having at least one basic function (Formula IIc).

The following non-limiting examples of compounds of Formula IIa, IIb,and IIc is provided to illustrate the nature of the compounds describedand is not intended to limit the disclosure to the particular compoundsdepicted below. For any of the following embodiments, A and B are asdescribed above and infra.

Formula IIa Examples

Gly-Gly-SPM which is a compound of Formula II wherein

-   -   R¹ is H,    -   X¹ and X² are each H, and    -   M is absent:

Lys-Lys-SPM which is a compound of Formula II wherein

-   -   R¹ is H,    -   X¹ and X² are each side chain of lysine (butylamine), and    -   M is absent.        Lys-Val-SPM which is a compound of Formula II wherein    -   R¹ is each H,    -   X¹ is the side chain of lysine (butylamine),    -   X² is the side chain of valine (isopropyl), and    -   M is absent:

Lys-Ser-SPM which is a compound of Formula II wherein

-   -   R¹ is H,    -   X¹ is the side chain of lysine (butylamine),    -   X² is the side chain of serine, and    -   M is absent:

Lys-Gly-SPM which is a compound of Formula II wherein

-   -   R¹ is H,    -   X¹ is the side chain of lysine (butylamine),    -   X² is the side chain of glycine, and    -   M is absent:

Lys-Leu-SPM which is a compound of Formula II wherein

-   -   R¹ is H,    -   X¹ is the side chain of lysine (butylamine),    -   X² is the side chain of leucine (isobutyl), and    -   M is absent:

Lys-His-SPM which is a compound of Formula II wherein

-   -   R¹ is H,    -   X¹ is the side chain of lysine (butylamine),    -   X² is the side chain of histidine (imidazole);    -   M is absent:

Illustrative structures for three embodiments of Formula IIa, where thedipeptide is Gly-Gly and the SPM is either LXA4, PDX, or AT-RvD1, areshown below:

Formula IIb Examples

In embodiments, M is a monovalent metal cation such as Na⁺ or K⁺(Formula IIb). Non-limiting examples of Formula lib compounds includethe following:

Na⁺-Gly-Gly-SPM which is a compound of Formula IIb wherein

-   -   R¹ is absent,    -   X¹ and X² are each H, and;    -   M is Na:

Illustrative structures for three embodiments of Formula IIb, where theSPM is either AT-RvD1, LXA4, or PDX, and M is a sodium cation, are shownbelow:

Formula IIc Examples

In embodiments, M is a non-metal molecule having at least one basicfunction, such as a monovalent amine-based cation, e.g.,tri-ethanolamine, or tri-ethylamine or a basic pharmaceutical compoundsuch as metformin or gabapentin. Non-limiting examples of Formula IIccompounds include the following:

Triethanolamine-Gly-Gly-SPM, which is a compound of Formula II wherein

-   -   R₁ is absent,    -   X¹ and X² are each H, and    -   M is trienthanolamine:

Metformin-Gly-Gly-SPM, which is a compound of Formula II wherein

-   -   R¹ is absent,    -   X¹ and X² are each H, and    -   M is metformin:

Formula III Compounds

In embodiments, the disclosure provides compounds of Formula III or anenantiomer, polymorph, solvate, or hydrate thereof:

-   -   wherein    -   R² is a C₁-C₁₀ alkyl comprising at least one basic function;    -   A and B are each independently an SPM molecule;    -   A and B may be the same or different; and    -   either A or B, but not both, may be absent.

In embodiments, R² is the side chain of an amino acid residue selectedfrom lysine, arginine, and glutamine. In embodiments, R² is the sidechain of lysine. In embodiments, R² is selected from the groupconsisting of —(CH₂)₃—NHC(NH₂ ⁺)NH₂, —(CH₂)₄—NH₃ ⁺, and —(CH₂)₂—C(O)NH₃⁺. In embodiments, R² is —(CH₂)₄—NH₃ ⁺

In embodiments, the basic function of R² is selected from the groupconsisting of a positively charged primary amine, a positively chargedsecondary amine, a positively charged tertiary amine, and a positivelycharged guanidine.

In embodiments, the basic function of R² refers to —NH₃, —NHC(NH₂+)NH₂,—NHR⁶R⁷, or —NR⁶R⁷R⁸, wherein R⁶, R⁷, R⁸ are each independentlyhydrogen, —CN, —COOH, —CONH₂, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl; R⁶ and R⁷ substituentsbonded to the same nitrogen atom may optionally be joined to form aunsubstituted heterocycloalkyl or unsubstituted heteroaryl. Inembodiments, the basic function is a positively charged amine. Inembodiments, the basic function is a primary amine. In embodiments, thebasic function is —NH₃ ⁺.

In embodiments, R² is the side chain of lysine, A and B are the samemolecule and are selected from the group consisting of RvD1, RvD2, RvE1,PDX, LXA4, AT-RvD1, AT-RvD2, AT-PD1, AT-RvE1, and AT-LXA4.

In embodiments, the SPM component (A, B) comprises or consists of an SPMselected from the group consisting of RvD1, AT-RvD1, RvD2, AT-RvD2,RvE1, AT-RvE1, PDX, AT-PD1, LXA4 and AT-LXA4. In embodiments, the SPMcomponent consists of RvE1, AT-RvE1, LXA4, or AT-LXA4. In embodiments,the SPM component consists of RvE1 or LXA4.

In embodiments, a compound of Formula III is a mono or bis SPM linearlysyl-lysine compound selected from the group consisting of RvE1 linearlys-lys, AT-RvE1 linear lys-lys, LXA4 linear lys-lys, AT-LXA4 linearlys-lys, RvD1 linear lys-lys, AT-RvD1 linear lys-lys, PDX linearlys-lys, and RvD2 linear lys-lys. In embodiments, a compound of FormulaIII is a mono or bis SPM lysyl-lysine compound selected from the groupconsisting of AT-RvD1 linear lys-lys, AT-RvD2 linear lys-lys, andAT-LXA4 linear lys-lys. In embodiments, a compound of Formula III is amono or bis SPM lysyl-lysine compound selected from the group consistingof RvE1 linear lys-lys, AT-RvE1 linear lys-lys, LXA4 linear lys-lys andAT-LXA4 linear lys-lys.

Exemplary compounds of Formula III are provided in Table 5. Inembodiments, a compound of Formula III is selected from the groupconsisting of Compounds 5, 10, 15, 20, 25, 30, 35, and 40 of Table 5. Inembodiments, a compound of Formula III is selected from the groupconsisting of Compounds 5 and 10 (RvE1 and AT-RvE1 embodiments) of Table5. In embodiments, a compound of Formula III is selected from the groupconsisting of Compounds 15 and 20 (LXA4 and AT-LXA4 embodiments) ofTable 5.

Formula IV Compounds

In embodiments, the disclosure provides compounds of Formula IV or anenantiomer, polymorph, solvate, or hydrate thereof:

-   -   wherein    -   M is a divalent metal;    -   A and B are each independently an SPM molecule;    -   A and B may be the same or different;    -   either A or B, but not both, may be absent;    -   R¹ and R² are each independently a C₁-C₁₀ alkyl comprising at        least one basic function;    -   X¹ and X² are each independently H or CO—Z and Z is a peptide        comprising 1 to 5 amino acids or a pharmaceutically acceptable        salt thereof;    -   when either A or B is absent:        -   one of R¹, R² and the two CO—Z's is protonated; or        -   one of the two H's is positively charged; and        -   the one of R¹, R² and the two CO—Z's that is protonated or            the one of the positively charged H's forms an ionic bond            with either A or B; and    -   when A and B are both present:        -   two of R¹, R² and the two CO—Z's are protonated; or        -   one of R¹, R² and the two CO—Z's is protonated, and one of            the two H's is positively charged; and        -   the two of R¹, R² and the two CO—Z's that are protonated or            the one of R¹, R² and the two CO—Z's that is protonated and            the positively charged H each respectively form an ionic            bond with A and B.

Compounds of Formula IV have two amino acid moieties coordinated arounda divalent metal cation as the amino acid component and one or two SPMmolecules as the SPM component. In embodiments, the divalent metalcation is Mg²⁺, Ca²⁺, Mn²⁺, Fe²⁺, Cu²⁺, Co²⁺, Ni²⁺, Mo²⁺ or Zn²⁺. Inembodiments, the divalent metal cation is Mg²⁺. In embodiments, thedivalent metal cation is Ca²⁺. In embodiments, the divalent metal cationis Zn²⁺.

In embodiments, the amino acid component includes or consists of lysineor arginine. In embodiments, the amino acid component includes lysine orarginine. In embodiments, the basic function of R¹ and R² is selectedfrom a primary amine, a secondary amine, a tertiary amine, and aguanidine. In embodiments, basic function refers to —NH₃, —NHC(NH₂⁺)NH₂, —NHR⁶R⁷, or —NR⁶R⁷R⁸, wherein R⁶, R⁷, R⁸ are each independentlyhydrogen, —CN, —COOH, —CONH₂, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl; R⁶ and R⁷ substituentsbonded to the same nitrogen atom may optionally be joined to form aunsubstituted heterocycloalkyl or unsubstituted heteroaryl. Inembodiments, the basic function is a hydrogen bond acceptor. Inembodiments, the basic function is a hydrogen bond donor. Inembodiments, the basic function is a positively charged amine.

In embodiments, R¹ and R² are each the side chain of an amino acidresidue having a basic function. In embodiments, R¹ and R² are the sameand the amino acid residue is lysine or arginine.

In embodiments, R¹ and R² are independently selected from —(CH₂)₃—Y¹,and —(CH₂)₄—Y², where Y¹ and Y² are each a basic function which may bethe same or different.

In embodiments, R¹ and R² are both —(CH₂)₄—Y², and Y² is —NH₃ ⁺.

In embodiments, R¹ and R² are both —(CH₂)₃—Y¹, and Y¹ is —NHC(NH₂ ⁺)NH₂.

In embodiments, R¹ is —(CH₂)₃—Y¹, Y¹ is —NHC(NH₂ ⁺)NH₂, Y² is—(CH₂)₄—Y², and Y² is —NH₃ ⁺. In embodiments, R¹ is —(CH₂)₄—Y², Y² is—NH₃ ⁺, R² is —(CH₂)₃—Y¹; and Y¹ is NHC(NH₂ ⁺)NH₂.

In embodiments, X¹ and X² are the same and are hydrogen (H). Inembodiments, X¹ is hydrogen. In embodiments, X² is hydrogen.

In embodiments, the SPM component (A,B) comprises or consists of an SPMselected from the group consisting of RvD1, AT-RvD1, RvD2, AT-RvD2,RvE1, AT-RvE1, PDX, AT-PD1, LXA4 and AT-LXA4. In embodiments, the SPMcomponent consists of RvE1, AT-RvE1, LXA4, or AT-LXA4. In embodiments,the SPM component consists of RvE1 or LXA4.

In embodiments, the compound of Formula IV is a mono or bis SPMmagnesium, calcium, or zinc di-lysinate (M-lys-lys, or M-di-lysinate)compound selected from the group consisting of RvD1 M-lys-lys, AT-RvD1M-lys-lys, RvD2 M-lys-lys, AT-RvD2 M-lys-lys, RvE1 M-lys-lys, AT-RvE1M-lys-lys, PDX M-lys-lys, LXA4 M-lys-lys, and AT-LXA4 M-lys-lys.

In embodiments, the compound of Formula IV is a mono or bis SPMMg-di-lysinate compound selected from the group consisting of RvE1Mg-lys-lys, AT-RvD1 Mg-lys-lys, RvD2 Mg-lys-lys, PDX Mg-lys-lys, andLXA4 Mg-lys-lys.

In embodiments, the compound of Formula IV is a mono or his RvE1Mg-lys-lys or a mono or bis AT-RvE1 Mg-lys-lys.

In embodiments, the compound of Formula IV is a mono or his LXA4Mg-lys-lys or a mono or bis AT-LXA4 Mg-lys-lys.

In embodiments, the compound of Formula IV is a mono or his SPMCa-di-lysinate compound selected from the group consisting of RvE1Ca-lys-lys, AT-RvE1 Ca-lys-lys, LXA4 Ca-lys-lys and AT-LXA4 Ca-lys-lys.

In embodiments, the compound of Formula IV is a mono or bis RvE1 Calys-lys or a mono or bis AT-RvE1 Ca lys-lys.

In embodiments, the compound of Formula IV is a mono or his LXA4Ca-lys-lys or a mono or his AT-LXA4 Ca-lys-lys.

In embodiments, the compound of Formula IV is a mono or his SPMZn-di-lysinate compound selected from the group consisting of RvE1Zn-lys-lys, AT-RvE1 Zn-lys-lys, LXA4 Zn-lys-lys and AT-LXA4 Zn-lys-lys.

In embodiments, the compound of Formula IV is a mono or bis RvE1 Znlys-lys or a mono or his AT-RvE1 Zn lys-lys.

In embodiments, the compound of Formula IV is a mono or his LXA4Zn-lys-lys or a mono or bis AT-LXA4 Zn-lys-lys.

Exemplary compounds of Formula IV are provided in Table 5. Inembodiments, a compound of Formula IV is selected from the groupconsisting of Compounds 1-3, 6-8, 11-13, 16-18, 21-23, 26-28, 31-33, and36-38 of Table 5. In embodiments, a compound of Formula IV is selectedfrom the group consisting of Compounds 1-3 and 6-8 of Table 5 (RvE1 andAT-RvE1 embodiments). In embodiments, a compound of Formula IV isselected from the group consisting of Compounds 11-13 and 16-18 of Table5 (LXA4 and AT-LXA4 embodiments). In embodiments, a compound of FormulaIV is selected from the group consisting of Compounds 21-23 and 26-28 ofTable 5 (RvD1 and AT-RvD1 embodiments).

The SPM Component

As used herein, the term “SPM” is used to refer to SPMs such asprotectins and resolvins, as well as lipoxins and aspirin-triggeredlipid mediators (e.g., aspirin-triggered lipoxins and protectins). Thesemolecules are described, for example in U.S. Pat. No. 5,441,951 and U.S.Pat. No. 8,119,691 (lipoxins and aspirin-triggered lipoxins), U.S. Pat.No. 6,670,396 (aspirin-triggered lipid mediators), US 2006-0293288(resolvins), U.S. Pat. No. 7,378,444 and U.S. Pat. No. 7,595,341(analogs of lipid mediators derived from omega-3 fatty acids).

Some specific examples of SPM molecules that may used to form the SPMcomponent of the compounds and compositions described here includemediators derived from arachidonic acid (AA) (Table 1), mediatorsderived from eicosapentaenoic acid (EPA) (Table 2); mediators derivedfrom docosahexaenoic acid (DHA) (Table 3); and aspirin-triggeredmediators (Table 4).

In embodiments, the SPM component of a compound or composition describedhere is selected from an arachidonic acid (AA) derived lipid mediator.In embodiments, the AA derived lipid mediator is selected from lipoxinA4 or lipoxin B4.

In embodiments, the SPM component of a compound or composition describedhere is selected from an eicosapentaenoic acid (EPA) derived lipidmediator. In embodiments, the EPA derived lipid mediator is selectedfrom lipoxin A5, lipoxin B5, resolvin E1, resolvin E2, and resolvin E3.

In embodiments, the SPM component of a compound or composition describedhere is selected from a docosahexaenoic acid (DHA) derived lipidmediator. In embodiments, the DHA derived lipid mediator is selectedfrom resolvin D1, resolvin D2, resolvin D3, resolvin D4, resolvin D5,resolvin D6, protectin D1, and protectin DX.

In embodiments, the SPM component of a compound or composition describedhere is selected from an aspirin-triggered lipid mediator. Inembodiments, the aspirin-triggered lipid mediator is selected from15-epi-lipoxin A4, 15-epi-lipoxin B4, aspirin-triggered resolvin D1,aspirin-triggered resolvin D2, aspirin-triggered resolvin D3,aspirin-triggered resolvin D4, aspirin-triggered resolvin D5,aspirin-triggered resolvin D6, and aspirin-triggered protectin D1.

In embodiments, the SPM component of a compound or composition describedhere is selected from a compound set forth in Table 1, Table 2, Table 3,or Table 4.

TABLE 1 Arachidonic Acid (AA) and Mediators Derived from AA Name AbbrevFormula Chemical Name Arachidonic AA C₂₀H₃₂O₂5Z,8Z,11Z,14Z-Eicosatetraenoic acid acid Lipoxin A4 LXA4 C₂₀H₃₂O₅5S,6R,15S-trihydroxy- 7E,9E,11Z,13E-eicosatetraenoic acid Lipoxin B4LXB4 C₂₀H₃₂O₅ 5S,14R,15S-trihydroxy- 6E,8Z,10E,12E-eicosatetraenoic Zacid

TABLE 2 EPA and Mediators Derived from EPA Name Abbrev. Formula ChemicalName Eicosapentaenoic acid EPA C₂₀H₃₀O₂5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid Lipoxin A5 LXA5 C₂₀H₃₀O₅5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid Lipoxin B5LXB5 C₂₀H₃₀O₅ 5S,14R,15S-trihydroxy-6E,8Z,10E,12E,17Z-eicosapentaenoicacid Resolvin E1 RvE₁ C₂₀H₃₀O₅5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid ResoivinE2 RvE₂ C₂₀H₃₀O₄ 5S,18R-dihydroxy-6E,8Z,11Z,14Z,16E-eicosapentaenoicacid Resolvin E3 RvE₃ C₂₀H₃₀O₄17R,18R-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid

TABLE 3 DHA and Mediators Derived from DHA Name Abbrev. Formula ChemicalName Docosahexaenoic acid DHA C₂₂H₃₂O₂4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid Resolvin D1 RvD1 C₂₂H₃₂O57S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid ResolvinD2 RvD2 C₂₂H₃₂O₅7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acidResolvin D3 RvD3 C₂₂H₃₂O₅4S,11R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-docosahexaenoic acid ResolvinD4 RvD4 C₂₂H₃₂O₅4S,5,17S-trihydroxy-6E,8E,10Z,13Z,15E,19Z-docosahexaenoic acid ResolvinD5 RvD5 C₂₂H₃₂O₄ 7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoicacid Resolvin D6 RvD6 C₂₂H₃₂O₄4S,17S-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid Protectin D1PD1 C₂₂H₃₂O₄ 10R,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoicacid Protectin DX PDX C₂₂H₃₂O₄10S,17S-dihydroxy-(4Z,7Z,11E,13Z,15E,19Z)-docosahexaenoic acid

TABLE 4 Aspirin-Triggered Mediators Name Abbrev. Formula Chemical Name15-epi-Lipoxin A4 AT-LXA4 C₂₀H₃₂O₅5S,6R,15R-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid 15-epi-LipoxinB4 AT-LXB4 C₂₀H₃₂O₅ 5S,14R,15R-trihydroxy-6E,8Z,10E,12E-eicosatetraenoicacid Aspirin-triggered AT-RvD1 C₂₂H₃₂O₅7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid ResolvinD1 Aspirin-triggered AT-RvD2 C₂₂H₃₂O₅7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acidResolvin D2 Aspirin-triggered AT-RvD3 C₂₂H₃₂O₅4S,11R,17R-trihydroxy-5Z,7E,9E,13Z,15E,19Z-docosahexaenoic acid ResolvinD3 Aspirin-triggered AT-RvD4 C₂₂H₃₂O₄4S,5,17R-trihydroxy-6E,8E,10Z,13Z,15E,19Z-docosahexaenoic acid ResolvinD4 Aspirin-triggered AT-RvD5 C₂₂H₃₂O₄7S,17R-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid Resolvin D5Aspirin-triggered AT-RvD6 C₂₂H₃₂O₄4S,17R-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid Resolvin D6Aspirin-triggered AT-RvE₁ C₂₀H₃₀O₅5S,12R,18S-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid ResolvinE1 Aspirin-triggered AT-PD1 C₂₂H₃₂O₄10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid ProtectinD1

In certain embodiments, the invention provides a solvate of a compounddescribed herein. A “solvate” refers to a form of salt bound by anon-covalent bond to another molecule (such as a polar solvent). Suchsolvates are typically crystalline solids having a substantially fixedmolar ratio of solute and solvent. When the solvent is water, thesolvate formed is a hydrate. Example hydrates include hemihydrates, monohydrates, dihydrates, etc.

In embodiments, the invention provides a crystalline form of a compounddescribed herein. In one embodiment, the invention provides a polymorphof an ionic salt described herein.

Physical Properties

The compounds described here and compositions comprising same possessadvantageous chemical and physical properties compared to the free SPMs.For example, in embodiments a compound described here may be stabilizedagainst chemical degradation compared to the corresponding free SPM. Inembodiments, the compounds are stable against chemical degradation,including oxidative degradation. In embodiments, the compounds arestable to degradation induced by exposure to air, oxygen, and humidityas evidenced by a lack of change in physical properties, such as flowcharacteristics, or in chemical properties, as measured e.g., byspectroscopic techniques such as nuclear magnetic resonance (NMR) orhigh pressure liquid chromatography (HPLC). In embodiments, theincreased stability is evidenced by a lack of chemical degradation after2, 4, or 8 weeks. In embodiments, a compound described here isstabilized against chemical degradation as evidenced by the lack ofdegradation products at 2 or 8 weeks, compared to the free SPM.

In embodiments, the compounds are physically solid, free flowingsubstances suitable for formulation into solid dosage forms such aspowders, tablets, capsules or caplets. In addition, the compounds andcompositions of the invention can be readily combined, e.g., by physicaladmixture, with other biologically active agents in a solid dosage form.

Pharmacokinetic Properties

In embodiments, the compounds described here demonstrate highlyfavorable pharmacokinetic properties. For example, in embodiments, thecompounds provide detectable levels of free SPMs in the blood or serumfollowing oral, or parenteral (including via intravenous,intra-arterial, or intramuscular injection) administration, as discussedin more detail in the examples, infra. In embodiments, the compounds ofthe invention formulated as oral dosage forms deliver higher amounts ofthe free SPM component to the blood/serum than is achievable with oraladministration of, for example, the free SPM itself.

Compositions

The present disclosure provides compositions including one or more ofthe compounds described herein, including compositions containingmixtures of two or more different compounds described herein. Inembodiments, a compound or mixture of compounds described here may beformulated as a pharmaceutical composition, or as a food additive orsupplement, meaning that the compound itself and any additives orexcipients in the formulation are suitable for administration to humansor animals. In embodiments, the composition is a pharmaceuticalcomposition. In embodiments, the composition is a non-pharmaceuticalcomposition.

A composition including one or more compounds of the invention may beformulated as a solid or liquid dosage form adapted for oral delivery.The oral dosage form may be in the form of a solid, such as a tablet, acapsule containing particulates, liquids, or powders, a lozenge(including liquid-filled), a gum, or a gel. In one embodiment, thedosage form is a solid oral dosage form. In embodiments, the compositionis a powder suitable for reconstitution in an aqueous liquid. Suchpowders may be used, for example, to prepare a liquid suitable forparenteral administration, e.g., via intravenous, intramuscular, orintraperitoneal injection.

In embodiments, a composition including one or more compounds describedhere may be formulated as a dosage form adapted for rectal delivery. Inembodiments, the dosage form adapted for rectal delivery is an ointment,suppository, or enema. In embodiments, the dosage form is adapted foronce a day delivery. In embodiments, the solid dosage form is adaptedfor delivery twice a day.

In embodiments, a composition comprising a compound of any one ofFormulas I-IV may be in the form of a unit dose of the compound. Inembodiments, the unit dose is in the form of tablet, capsule,suppository, or enema. In embodiments, the unit dose contains from 1microgram (ug) to 50 milligrams (mg) of the SPM that forms the SPMcomponent of the compound of Formula I, II, III, or IV. In embodiments,the compound is a compound of Formula I or IV. In embodiments, the unitdose contains 1, 5, 10, 25, 50, 100, 250, or 500 micrograms of the SPM.In embodiments, the unit dose contains 1, 5, 10, or 20 milligrams of theSPM.

In embodiments of Formula I, the SPM component of the compound consistsof from 50% to 75% by weight of the SPM. In an embodiment of Formula I,the compound is a mono SPM salt of lysyl lysine, the SPM is selectedfrom RvD1, RvD2, RvE1, PDX, LXA4, AT-PD1, AT-RvD1, AT-RvD2, AT-LXA4, andAT-RvE1, and the SPM comprises from 50-60%0/by weight of the compound.In an embodiment of Formula I, the compound is a bis salt and the SPMcomprises from 60-75% by weight of the compound.

In embodiments of Formula IV, the SPM component of the compound consistsof from 50% to 75% by weight of the SPM. In an embodiment of Formula IV,the compound is a bis SPM magnesium di-lysinate (Mg-lys-lys) salt of anSPM selected from RvD1, RvD2, RvE1, PDX, LXA4, AT-PD1, AT-RvD1, AT-RvD2,AT-LXA4, and AT-RvE1 and the SPM comprises from 60-75% by weight of thecompound. In embodiments where the SPM is a mono salt, the SPM comprisesfrom about 50-60% by weight of the compound. In embodiments, the SPM isRvE1 or AT-RvE1 and the SPM comprises about 65% by weight of thecompound. In embodiments, the SPM is RvD1, RvD2, AT-RvD1, or AT-RVD2 andthe SPM comprises about 70% by weight of the compound.

The compounds described here may be formulated alone or in combinationwith one or more additional active pharmaceutical ingredients (API) orbiologically active agents. Also provided are compositions including oneor more of the compounds described herein, or mixtures of same, alongwith a second active agent. In embodiments the second active agent is abiologically active agent or an active pharmaceutical ingredient (API).In embodiments, a compound described here is formulated with one or moreadditional APIs or biologically active agents in a single dosage form.In embodiments, the dosage form is a solid or liquid dosage form. Inembodiments, the solid dosage form is a powder suitable forreconstitution in aqueous media. In embodiments, the solid dosage formis an ointment, suppository, or enema.

Depending on the nature of the compounds and excipients making up thecompositions described here, the composition may be suitable forpharmaceutical or veterinary use, or for use a dietary additive orsupplement, or any combination of these uses. To the extent the variouscompositions are discussed in the following sections as “pharmaceuticalcompositions” or “additives and supplements” these terms are not meantto be limiting, only descriptive.

The compositions described here may be formulated using one or moresuitable excipients or carriers. A suitable excipient or carrier is onesuitable for human or animal use. The term “excipient” refers to anadditive that serves some purpose in the composition other than acarrier, for example as a stabilizer, taste masking agent (e.g., asweetener), solubilizing agent, or suspending agent. Often, a carrierwill serve a dual purpose as a simple carrier or diluent and anexcipient. Examples of pharmaceutically acceptable excipients may thusinclude carriers. Non-limiting examples of excipients for use in thecompositions of the invention include sterile liquids, water, bufferedsaline, ethanol, polyols (for example, glycerol, propylene glycol,liquid polyethylene glycol and the like), oils, detergents, suspendingagents, carbohydrates (e.g., glucose, lactose, sucrose or dextran),antioxidants (e.g., ascorbic acid or glutathione), chelating agents, lowmolecular weight proteins, and suitable mixtures thereof.

A suitable excipient or carrier is typically a pharmaceuticallyacceptable carrier or excipient for use in animals or humans (or both).The term “pharmaceutically acceptable” indicates approval by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia such as theEuropean Pharmacopeia, for use in animals, and more particularly inhumans. In the context of the pharmaceutical compositions of theinvention, a “carrier” refers to, for example, a solvent, a diluent, orvehicle with which the ionic salt of the invention is formulated fordelivery. Examples of pharmaceutically acceptable carriers for use inthe compositions of the invention include, without limitation, sterileaqueous and non-aqueous liquids, water, buffered saline, ethanol,polyols (for example, glycerol, propylene glycol, liquid polyethyleneglycol and the like), and oils, for liquid dosage forms; orcarbohydrates (e.g., glucose, lactose, sucrose or dextran) for soliddosage forms.

The compounds described here may be formulated in any suitable form andfor any suitable intended route of administration. Typically, the dosageform is at least in part determined by the intended route ofadministration. In embodiments, a compound described here is formulationfor administration by an oral, rectal, or parenteral route.

In one embodiment, the dosage form is a liquid suitable foradministration to the eye. The formulation may be a solution,suspension, or gel suitable for ocular administration, e.g., suitablefor topical administration to the eye, also referred to as an ophthalmicformulation.

In one embodiment, the ophthalmic formulation is an aqueous formulation.In one embodiment, the ophthalmic formulation comprises one or more ofglycerin, hypromellose, propylene glycol or polyethylene glycol. In oneembodiment, the ophthalmic formulation further comprises one or more ofpolysorbate 80, carbomer copolymer type A, purified water, sodiumhydroxide, ascorbic acid, benzalkonium chloride, boric acid, dextrose,disodium phosphate, glycine, magnesium chloride, potassium chloride,sodium borate, sodium chloride, sodium citrate, sodium lactate, edetatedisodium, hydrochloric acid, sodium hydroxide, aminornethylpropanol,hydroxypropyl guar, polyquaternium-I, or sorbitol.

In one embodiment, the ophthalmic formulation comprises one or more ofsurfactants, tonicity agents, buffers, preservatives, co-solvents andviscosity building agents. Various tonicity agents may be employed toadjust the tonicity of the composition, preferably to that of naturaltears for ophthalmic compositions. For example, sodium chloride,potassium chloride, magnesium chloride, calcium chloride, dextroseand/or mannitol may be added to the composition to approximatephysiological tonicity. Preferably, the tonicity agent is present in anamount sufficient to cause the final composition to have anophthalmically acceptable osmolality (generally about 150-450 mOsm,preferably 250-350 mOsm). An appropriate buffer system (e.g., sodiumphosphate, sodium acetate, sodium citrate, sodium borate or boric acid)may be added to the compositions to prevent pH drift under storageconditions. The particular concentration will vary, depending on theagent employed. Preferably, however, the buffer will be chosen tomaintain a target pH within the range of pH 6-7.5.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers.

In embodiments, the composition is a pharmaceutical compositionincluding a compound described herein, or any mixture thereof, andoptionally a pharmaceutically acceptable carrier and/or excipient. Inembodiments, the composition further comprises an additional activeagent, such as an API, as described below.

In one embodiment is provided a solid dosage form including a compoundof the invention in physical admixture with one or more additionalactive pharmaceutical ingredients (APIs). In embodiments, the one ormore additional APIs is an antihyperlipidemic agent, an anti-diabeticagent, an anti-epileptic agent, or an anti-inflammatory agent. In oneembodiment the API is an antihyperlipidemic agent or an anti-diabeticagent. In one embodiment, the antihyperlipidemic agent is selected fromthe group consisting of an HMG CoA enzyme inhibitor (e.g., a statin), acholesterol absorption inhibitor, and a cholesterol esterase transferprotein (CETP) inhibitor. In one embodiment, the antihyperlipidemicagent is a statin. In one embodiment, the statin is selected from thegroup consisting of atorvastatin, risuvostatin, simvastatin,pravastatin, and pharmaceutically acceptable salts or prodrugs thereof.In one embodiment, the statin is present in an amount ranging from 5 mgto 100 mg. In one embodiment, the statin is pravastatin. In oneembodiment, the antihyperlipidemic agent is a cholesterol absorptioninhibitor. In one embodiment, the cholesterol absorption inhibitor isezetimibe, also known as Zetia. In one embodiment, theantihyperlipidemic agent is a CETP inhibitor. In one embodiment, theCETP inhibitor is anacetrapib, or a hydrate, or solvate thereof.

The pharmaceutical compositions including a compound described here, andmixtures thereof, are useful in methods of treating various diseases anddisorders that are responsive to treatment with SPMs, their derivatives,and analogs. These uses are described in more detail infra.

Enteral Formulations

In embodiments, a pharmaceutical composition including a compounddescribed here, and mixtures thereof, is formulated as an enteral dosageform. In embodiments, the enteral dosage form is selected from an oralor rectal formulation. The oral formulation may be in the form of e.g.,a tablet, solution, suspension, or emulsion. The rectal formulation maybe in the form of e.g., an ointment, suppository, or enema.

Parenteral Formulations

In embodiments, a pharmaceutical composition including a compounddescribed here, and mixtures thereof, is formulated as a parenteraldosage form. In embodiments, the parenteral dosage form is selected froman intravenous dosage form, an intra-arterial dosage form, or anintramuscular dosage form. In accordance with any of these embodiments,the dosage form may be in the form of a clear aqueous solution or in theform of a lyophilized solid, e.g., contained in container, such as avial or an ampule which is suitable for reconstitution with a specifiedamount of sterile water or aqueous buffer for administration by aparenteral route, e.g., intravenous, intra-arterial, or anintramuscular.

Ophthalmic Formulations

In embodiments, the compounds described herein are useful for treatingor ameliorating one or more symptoms of an ocular disease or disorder,as described in more detail below. Accordingly, the invention providescompounds of any one of Formulas I-VI in a pharmaceutical compositionsuitable for topical administration to the eye, also referred to as anophthalmic formulation. The formulation may be a solution, suspension,or gel suitable for ocular administration.

In one embodiment, the ophthalmic formulation is an aqueous formulation.In one embodiment, the ophthalmic formulation comprises one or more ofglycerin, hypromellose, propylene glycol or polyethylene glycol. In oneembodiment, the ophthalmic formulation further comprises one or more ofpolysorbate 80, carbomer copolymer type A, purified water, sodiumhydroxide, ascorbic acid, benzalkonium chloride, boric acid, dextrose,disodium phosphate, glycine, magnesium chloride, potassium chloride,sodium borate, sodium chloride, sodium citrate, sodium lactate, edetatedisodium, hydrochloric acid, sodium hydroxide, aminornethylpropanol,hydroxypropyl guar, polyquaternium-L or sorbitol.

In one embodiment, the ophthalmic formulation comprises one or more ofsurfactants, tonicity agents, buffers, preservatives, co-solvents andviscosity building agents. Various tonicity agents may be employed toadjust the tonicity of the composition, preferably to that of naturaltears for ophthalmic compositions. For example, sodium chloride,potassium chloride, magnesium chloride, calcium chloride, dextroseand/or mannitol may be added to the composition to approximatephysiological tonicity. Preferably, the tonicity agent is present in anamount sufficient to cause the final composition to have anophthalmically acceptable osmolality (generally about 150-450 mOsm,preferably 250-350 mOsm). An appropriate buffer system (e.g., sodiumphosphate, sodium acetate, sodium citrate, sodium borate or boric acid)may be added to the compositions to prevent pH drift under storageconditions. The particular concentration will vary, depending on theagent employed. Preferably, however, the buffer will be chosen tomaintain a target pH within the range of pH 6-7.5.

Compositions formulated for the treatment of dry eye-type diseases anddisorders may also comprise aqueous carriers designed to provideimmediate, short-term relief of dry eye-type conditions. Such carrierscan be formulated as a phospholipid carrier or an artificial tearscarrier, or mixtures of both. As used herein, “phospholipid carrier” and“artificial tears carrier” refer to aqueous compositions which: (i)comprise one or more phospholipids (in the case of phospholipidcarriers) or other compounds, which lubricate, “wet,” approximate theconsistency of endogenous tears, aid in natural tear build-up, orotherwise provide temporary relief of dry eye symptoms and conditionsupon ocular administration; (ii) are safe; and (iii) provide theappropriate delivery vehicle for the topical administration of aneffective amount of one or more of the fatty acid salts of theinvention.

Examples or artificial tears compositions useful as artificial tearscarriers include, but are not limited to, commercial products, such asTears Naturale™, Tears Naturale n™, Tears Naturale Free™, and BionTears™. (Alcon Laboratories, Inc., Fort Worth, Tex.). Examples ofphospholipid carrier formulations include those disclosed in U.S. Pat.No. 4,804,539 (Guo et al.), U.S. Pat. No. 4,883,658 (Holly), U.S. Pat.No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S.Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek etal.), U.S. Pat. No. 5,371,108 (Korb et al.), U.S. Pat. No. 5,578,586(Gionek et al.); the foregoing patents are incorporated herein byreference to the extent they disclose phospholipid compositions usefulas phospholipid carriers of the present invention.

Other compounds designed to lubricate, “wet,” approximate theconsistency of endogenous tears, aid in natural tear build-up, orotherwise provide temporary relief of dry eye symptoms and conditionsupon ocular administration the eye are known in the art. Such compoundsmay enhance the viscosity of the composition, and include, but are notlimited to: monomeric polyols, such as, glycerol, propylene glycol,ethylene glycol; polymeric polyols, such as, polyethylene glycol,hydroxypropylmethyl cellulose (“HPMC”), carboxy methylcellulose sodium,hydroxy propylcellulose (“HPC”), dextrans, such as, dextran 70; watersoluble proteins, such as gelatin; and vinyl polymers, such as polyvinylalcohol, polyvinylpyrrolidone, povidone and carbomers, such as carbomer934P, carbomer 941, carbomer 940, carbomer 974P.

Examples of viscosity enhancing agents include, but are not limited topolysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily; vinyl polymers; and acrylic acid polymers. In general, thephospholipid carrier or artificial tears will exhibit a viscosity of 1to 400 centipoises (“cps”). Topical ophthalmic products are typicallypackaged in multidose form. Preservatives may be required to preventmicrobial contamination during use. Suitable preservatives includebenzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbicacid, polyquaternium-1, or other agents known to those skilled in theart. Such preservatives are typically employed at a level of from 0.001to 1.0% w/v. Unit dose compositions of the present invention will besterile, but typically unpreserved. Such compositions, therefore,generally will not contain preservatives.

Other wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, and perfumingagents, preservatives andantioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, a-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

A contact lens may optionally be used to allow for extravasation ofvasoactive substance over a more prolonged time period. Vasoactivesubstances such as Thrombin and Thromboxane A may further induceincrease in tear volume via venular vasoconstriction and increasedperfusion through lacrimal, accessory lacrimal and surface microvessels;where increased paracellular endothelial openings that increasecapillary permeability can further enhance this benefit.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers.

Pharmaceutical Uses

The compounds and compositions described here are useful in methods oftreating diseases and disorders characterized by excessive inflammation.For example, the compounds and compositions described here are useful intreating chronic diseases characterized by excessive inflammationincluding gastrointestinal diseases and disorders, infectious diseases,pulmonary and vascular diseases and disorders, metabolic diseases anddisorders, and neurological diseases and disorders. Accordingly, thedisclosure provides a method of treating a disease or disordercharacterized by excessive inflammation, the method comprisingadministering to a subject in need thereof, preferably a human subject,an amount of a compound of Formula I, II, II, IV effective to treat thedisease or disorder. In accordance with any of the embodiments of themethods described here, the compound may be administered in the form ofa pharmaceutical composition, or a veterinary composition, or anutritional additive or supplement.

In embodiments, the disclosure provides a method of treating agastrointestinal disease or disorder selected from the group consistingof inflammatory bowel disease (IBD), ulcerative colitis, Crohn'sdisease, proctitis, pouchitis, Crohn's disease of the pouch,eosinophilic colitis, lymphocytic colitis, collagenous colitis,diversion colitis, chemical colitis, ischemic colitis, infectiouscolitis, pseudomembranous colitis and indeterminate colitis, the methodcomprising administering an amount of a Compound of Formulas I-IV,effective to treat the disease or disorder. In embodiments, the diseaseor disorder is an IBD-related disease or disorder selected fromulcerative colitis, Crohn's disease, proctitis, pouchitis, Crohn'sdisease of the pouch, eosinophilic colitis, lymphocytic colitis,collagenous colitis, diversion colitis, chemical colitis, and ischemiccolitis. In embodiments, the IBD-related disease or disorder isulcerative colitis or Crohn's disease. In embodiments, the IBD-relateddisease or disorder is pouchitis.

In embodiments, the disclosure provides a method of treating agastrointestinal disease or disorder selected from the group consistingof bowel obstruction, chronic pancreatitis, colitis, colon cancer,congenital gastrointestinal anomalies, gastroschisis, high-outputfistula, parenteral nutrition associated liver disease, postoperativeileus (POI), postoperative intestinal inflammation, short bowelsyndrome, and sporadic polyposis.

In embodiments, the gastrointestinal disease or disorder is an IBDrelated disease or disorder as described above. In embodiments, thedisclosure provides a method of treating the IBD related disease ordisorder by administering to a human patient in need thereof a compoundof Formulas I-IV. In embodiments, the compound is a compound of FormulaI or IV.

In embodiments of the methods described here, the compound administeredis selected from a lysyl-lysine dipeptide of Formula I where A and B arethe same and are selected from the group consisting of RvD1, RvD2, RvE1,PDX, LXA4, AT-RvD1, AT-RvD2, AT-LXA4, and AT-RvE1. In embodiments, thecompound is selected from the group consisting of mono or bis RvE1 lysyllysine, mono or his AT-RvE1 lysyl lysine, mono or his LXA4 lysyl lysine,mono or bis AT-LXA4 lysyl lysine, mono or bis RvD1 lysyl lysine, mono orbis AT-RvD1 lysyl lysine, mono or bis RvD2 lysyl lysine, mono or hisAT-RvD2 lysyl lysine, mono or bis PDX lysyl lysine. In embodiments, thecompound is selected from the group consisting of mono or bis RvE1 lysyllysine, mono or bis AT-RvE1 lysyl lysine, mono or his LXA4 lysyl lysine,and mono or bis AT-LXA4 lysyl lysine.

In embodiments, the compound administered is selected from alysyl-lysine dipeptide of Formula I where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is an IBD related disease or disorder asdescribed above. In embodiments, the IBD-related disease or disorder isulcerative colitis or Crohn's disease. In embodiments, the IBD-relateddisease or disorder is pouchitis.

In embodiments, the compound administered is selected from alysyl-lysine dipeptide of Formula I where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is a gastrointestinal disease or disorderselected from eosinophilic esophagitis, Behcet's disease, irritablebowel syndrome, Celiac disease, intestinal mucositis, diverticulitis,and short bowel syndrome. In embodiments, the gastrointestinal diseaseor disorder is intestinal mucositis.

In embodiments, the compound administered is selected from alysyl-lysine dipeptide of Formula I where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is a dermatological disease or disorderselected from dermatitis, diabetic wound, eczema, pruritus, healingwound, acne, and steroid-induced rosacea. In embodiments, thedermatological disease or disorder is selected from dermatitis, eczema,pruritis, acne, and steroid-induced rosacea.

In embodiments, the compound administered is selected from alysyl-lysine dipeptide of Formula I where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is an inflammatory disease or disorderselected from asthma, ischemia reperfusion injury, lyme arthritis,periodontitis, peritonitis, psoriasis, rheumatoid arthritis,scleroderma, oral mucositis, stomatitis, chelitis, glossitis, Sjogren'ssyndrome and systemic inflammatory response syndrome. In embodiments,the inflammatory disease or disorder selected from asthma, psoriasis,scleroderma, and oral mucositis.

In embodiments, the compound administered is selected from alysyl-lysine dipeptide of Formula I where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is a neurological disease or disorderselected from postoperative delirium, acute postsurgical pain,fibromyalgia, endometriosis, vulvodynia, chronic lower back pain,treatment or management of pain associated with osteoarthritis, diabeticperipheral neuropathy and musculoskeletal injury or trauma.

In embodiments of the methods described here, the compound administeredis selected from a linear lysyl-lysine dipeptide of Formula III where Aand B are the same and are selected from the group consisting of RvD1,RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2, AT-LXA4, and AT-RvE1. Inembodiments, the compound is selected from the group consisting of monoor bis RvE1 linear lysyl lysine, mono or bis AT-RvE1 linear lysyllysine, mono or his LXA4 linear lysyl lysine, mono or his AT-LXA4 linearlysyl lysine, mono or bis RvD1 linear lysyl lysine, mono or bis AT-RvD1linear lysyl lysine, mono or his RvD2 linear lysyl lysine, mono or bisAT-RvD2 linear lysyl lysine, mono or bis PDX linear lysyl lysine. Inembodiments, the compound is selected from the group consisting of monoor his RvE1 linear lysyl lysine, mono or bis AT-RvE1 linear lysyllysine, mono or bis LXA4 linear lysyl lysine, and mono or his AT-LXA4linear lysyl lysine.

In embodiments, the compound administered is selected from a linearlysyl-lysine dipeptide of Formula III where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is an IBD related disease or disorder asdescribed above. In embodiments, the IBD-related disease or disorder isulcerative colitis or Crohn's disease. In embodiments, the IBD-relateddisease or disorder is pouchitis.

In embodiments, the compound administered is selected from a linearlysyl-lysine dipeptide of Formula III where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is a gastrointestinal disease or disorderselected from eosinophilic esophagitis, Behcet's disease, irritablebowel syndrome, Celiac disease, intestinal mucositis, diverticulitis,and short bowel syndrome. In embodiments, the gastrointestinal diseaseor disorder is intestinal mucositis.

In embodiments, the compound administered is selected from a linearlysyl-lysine dipeptide of Formula III where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is a dermatological disease or disorderselected from dermatitis, diabetic wound, eczema, pruritus, healingwound, acne, and steroid-induced rosacea. In embodiments, thedermatological disease or disorder is selected from dermatitis, eczema,pruritis, acne, and steroid-induced rosacea.

In embodiments, the compound administered is selected from a linearlysyl-lysine dipeptide of Formula III where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is an inflammatory disease or disorderselected from asthma, ischemia reperfusion injury, lyme arthritis,periodontitis, peritonitis, psoriasis, rheumatoid arthritis,scleroderma, oral mucositis, stomatitis, chelitis, glossitis, Sjogren'ssyndrome and systemic inflammatory response syndrome. In embodiments,the inflammatory disease or disorder selected from asthma, psoriasis,scleroderma, and oral mucositis.

In embodiments, the compound administered is selected from a linearlysyl-lysine dipeptide of Formula III where A and B are the same and areselected from the group consisting of RvE1, LXA4, AT-LXA4, and AT-RvE1,and the disease or disorder is a neurological disease or disorderselected from postoperative delirium, acute postsurgical pain,fibromyalgia, endometriosis, vulvodynia, chronic lower back pain,treatment or management of pain associated with osteoarthritis, diabeticperipheral neuropathy and musculoskeletal injury or trauma.

In embodiments of the methods described here, the compound administeredis selected from a magnesium, calcium, or zinc di-lysinate of Formula IVwhere A and B are the same and are selected from the group consisting ofRvD1, RvD2, RvE1, PDX, LXA4, AT-RvD1, AT-RvD2, AT-LXA4, and AT-RvE1. Inembodiments, the compound is selected from the group consisting of monoor his RvE1 Mg-di-lysinate, mono or bis AT-RvE1 Mg-di-lysinate, mono orbis LXA4 Mg-di-lysinate, mono or bis AT-LXA4 Mg-di-lysinate, mono or bisRvD1 Mg-di-lysinate, mono or bis AT-RvD1 Mg-di-lysinate, mono or bisRvD2 Mg-di-lysinate, mono or his AT-RvD2 Mg-di-lysinate and mono or hisPDX Mg-di-lysinate. In embodiments, the compound is selected from thegroup consisting of mono or bis RvE1 Mg-di-lysinate, mono or bis AT-RvE1Mg-di-lysinate, mono or his LXA4 Mg-di-lysinate, and mono or his AT-LXA4Mg-di-lysinate.

In embodiments, the compound administered is selected from a magnesium,calcium, or zinc di-lysinate of Formula IV where A and B are the sameand are selected from the group consisting of RvE1, LXA4, AT-LXA4, andAT-RvE1, and the disease or disorder is an IBD related disease ordisorder as described above. In embodiments, the IBD-related disease ordisorder is ulcerative colitis or Crohn's disease. In embodiments, theIBD-related disease or disorder is pouchitis.

In embodiments, the compound administered is selected from a magnesium,calcium, or zinc di-lysinate of Formula IV where A and B are the sameand are selected from the group consisting of RvE1, LXA4, AT-LXA4, andAT-RvE1, and the disease or disorder is a gastrointestinal disease ordisorder selected from eosinophilic esophagitis, Behcet's disease,irritable bowel syndrome, Celiac disease, intestinal mucositis,diverticulitis, and short bowel syndrome. In embodiments, thegastrointestinal disease or disorder is intestinal mucositis.

In embodiments, the compound administered is selected from a magnesium,calcium, or zinc di-lysinate of Formula IV where A and B are the sameand are selected from the group consisting of RvE1, LXA4, AT-LXA4, andAT-RvE1, and the disease or disorder is a dermatological disease ordisorder selected from dermatitis, diabetic wound, eczema, pruritus,healing wound, acne, and steroid-induced rosacea. In embodiments, thedermatological disease or disorder is selected from dermatitis, eczema,pruritis, acne, and steroid-induced rosacea.

In embodiments, the compound administered is selected from a magnesium,calcium, or zinc di-lysinate of Formula IV where A and B are the sameand are selected from the group consisting of RvE1, LXA4, AT-LXA4, andAT-RvE1, and the disease or disorder is an inflammatory disease ordisorder selected from asthma, ischemia reperfusion injury, lymearthritis, periodontitis, peritonitis, psoriasis, rheumatoid arthritis,scleroderma, oral mucositis, stomatitis, chelitis, glossitis, Sjogren'ssyndrome and systemic inflammatory response syndrome. In embodiments,the inflammatory disease or disorder selected from asthma, psoriasis,scleroderma, and oral mucositis.

In embodiments, the compound administered is selected from a magnesium,calcium, or zinc di-lysinate of Formula IV where A and B are the sameand are selected from the group consisting of RvE1, LXA4, AT-LXA4, andAT-RvE1, and the disease or disorder is a neurological disease ordisorder selected from postoperative delirium, acute postsurgical pain,fibromyalgia, endometriosis, vulvodynia, chronic lower back pain,treatment or management of pain associated with osteoarthritis, diabeticperipheral neuropathy and musculoskeletal injury or trauma.

Additional uses are described infra.

In the context of the methods described here, the term “treating” or“effective to treat” may refer to the amelioration or stabilization ofone or more symptoms associated with the disease or disorder beingtreated. The term “treating” may also encompass the management of adisease or disorder, referring to the beneficial effects that a subjectderives from a therapy which does not result in a cure of the underlyingdisease or disorder. The compositions of the invention can also be usedin the prevention of certain diseases, disorders, and conditions. Inthis context, the term “prevention” refers to preventing the recurrence,development, progression or onset of one or more symptoms of thedisease, disorder, or condition.

In accordance with the methods described here, a therapeuticallyeffective amount of a compound described herein is administered to asubject, the therapeutically effective amount being an amount of thecompound (or mixture of two or more compounds) sufficient to treat thedisease or disorder, or sufficient to achieve a desired therapeuticoutcome, for example the amelioration or stabilization of one or moresymptoms of the disease or disorder being treated, or in the context ofprevention, the amount sufficient to achieve prevention of therecurrence, development, progression or onset of one or more symptoms ofthe disease, disorder, or condition.

In the context of any of the methods of the present invention, thesubject may be a human or a non-human mammal. The non-human mammal maybe, for example, a non-human primate, a dog, cat, a rodent (e.g., amouse, a rat, a rabbit), a horse, a cow, a sheep, a goat, a bird, achicken, or any other non-human mammal. Preferably, the subject is ahuman.

In embodiments, the subject is a human subject. In one embodiment, thehuman is an adult human, a pediatric human, or a geriatric human, asthose terms are understood by the medical practitioner, for example asdefined by the U.S. Food and Drug Administration.

The compounds or compositions described here can be used as monotherapyor adjunctive therapy. The compositions of the invention can beadministered alone or in combination with one or more additionaltherapeutic agents (i.e., additional APIs) or therapies, for example aspart of a therapeutic regimen that includes, e.g., aspects of diet andexercise. In certain embodiments, the methods of the invention includeadministration of a composition of the invention as the primary therapy.In other embodiments, the administration of a composition of theinvention is an adjuvant therapy. In either case, the methods of theinvention contemplate the administration of a composition of theinvention in combination with one or more additional therapeutic agentsand/or therapies for the treatment or prevention of a disease ordisorder. The terms “therapy” and “therapies” refer to any method,protocol and/or agent that can be used in the prevention, treatment,management or amelioration of a disease or disorder, or one or moresymptoms thereof.

The compounds or compositions described here can also be used incombination therapy. As used herein, “combination therapy” or“co-therapy” includes the administration of a therapeutically effectiveamount of one or more of the compounds described here as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of the one or more compounds and an additional activeagent, for example an additional API or active biological agent asdescribed above. The beneficial effect of the combination includes, butis not limited to, pharmacokinetic or pharmacodynamic co-actionresulting from the combination. The beneficial effect of the combinationmay also relate to the mitigation of toxicity, side effect, or adverseevent associated with another agent in the combination. “Combinationtherapy” is not intended to encompass the administration of two or morecompounds as part of separate monotherapy regimens that incidentally andarbitrarily result in a beneficial effect that was not intended orpredicted.

Dermatological Conditions and Disorders

In embodiments, the present disclosure provides a method for treating adermatological condition or disorder in a subject in need thereof byadministering to the subject an effective amount of a compound of anyone of Formulas I-VI, or mixtures thereof, or a composition comprisingsame.

In embodiments, the dermatological disorder is dermatitis.

In embodiments, the dermatological condition is a diabetic wound.

In embodiments, the dermatological disorder is eczema.

In embodiments, the dermatological disorder is pruritus.

In embodiments, the dermatological condition is a healing wound.

In embodiments, the dermatological condition is acne.

In embodiments, the dermatological condition is steroid-induced rosacea.

Gastrointestinal Diseases and Disorders

In embodiments, the present disclosure provides a method for treating agastrointestinal disease or disorder in a subject in need thereof byadministering to the subject an effective amount of a compound of anyone of Formulas I-VI, or mixtures thereof, or a composition comprisingsame.

In embodiments, gastrointestinal disease or disorder is selected fromIBD, ulcerative colitis, Crohn's disease, proctitis, pouchitis, Crohn'sdisease of the pouch, eosinophilic colitis, lymphocytic colitis,collagenous colitis, diversion colitis, chemical colitis, ischemiccolitis, infectious colitis, pseudomembranous colitis and indeterminatecolitis. In embodiments, the gastrointestinal disease or disorder isselected from IBD, ulcerative colitis, and Crohn's disease.

In embodiments, the gastrointestinal disease or disorder is selectedfrom bowel obstruction, chronic pancreatitis, colitis, colon cancer,congenital gastrointestinal anomalies, gastroschisis, high-outputfistula, parenteral nutrition associated liver disease, postoperativeileus, postoperative intestinal inflammation, short bowel syndrome, andsporadic polyposis. In embodiments, the gastrointestinal disease ordisorder is selected from eosinophilic esophagitis, Behcet's disease,irritable bowel syndrome, celiac disease, Intestinal mucositis, NSAIDenteropathies, enteric infections, diverticulosis, diverticulitis,gastritis, pancreatitis, viral gastroenteritis, and Whipple's disease.

In embodiments, the gastrointestinal disease or disorder ispostoperative intestinal inflammation, postoperative ileus, or acombination thereof. In embodiments, the gastrointestinal inflammatorydisease or disorder is postoperative ileus (POI).

Infectious Diseases and Disorders Caused by an Infectious Agent

In embodiments, the present disclosure provides a method for treating adisease or disorder caused by an infectious agent, such as a bacterium,a fungus, or a virus, in a subject in need thereof by administering tothe subject an effective amount of a compound of any one of FormulasI-V, or mixtures thereof, or a composition comprising same.

In embodiments, the disease or disorder is a bacterial infection. Inembodiments, the bacterial infection is bacterial pneumonia. Inembodiments, the bacterial infection is an E. coli infection. Inembodiments, the bacterial infection is a Mycobacterium tuberculosisinfection.

In embodiments, the disease or disorder is a yeast infection. Inembodiments, the yeast infection is a Candida yeast infection.

In embodiments, the disease or disorder is sepsis. In embodiments, thesepsis is burn wound sepsis.

Inflammatory Disorders

The compounds described here may be particularly useful in the treatmentof diseases and disorders having a significant inflammatory component,due to the ability of the SPMs to mediate resolution of inflammation,and the ability of the compounds described here to delivertherapeutically effective amounts of SPMs to the tissue of a subject inneed of treatment for inflammation. In addition, the compounds andcompositions described here are useful in treating conditions whichwould benefit from rapid resolution of inflammation. Thus, the compoundsand compositions described here are useful in promoting wound healing,including the healing of burn wounds and diabetic wounds. Otherconditions which may be treated according to the methods described hereinclude, chronic pancreatitis, dermatitis, peritonitis, dry eye,bacterial infection, adipose tissue inflammation, localized aggressiveperiodontitis, temporomandibular joint inflammation, arthritis,postoperative pain, postsurgical cognitive decline, endotoxin shock,HSV-keratitis, allograft rejection, and heart ischemia.

In embodiments, the present disclosure provides a method for treating aninflammatory disease or disorder in a subject in need thereof byadministering to the subject an effective amount of a compound of anyone of Formulas I-VI, or mixtures thereof, or a composition comprisingsame. In embodiments, the effective amount is effective to treat one ormore symptoms of the inflammatory disease or disorder.

In embodiments, the inflammatory disease or disorder is selected fromthe group consisting of asthma, ischemia reperfusion injury, lymearthritis, periodontitis, peritonitis, psoriasis, rheumatoid arthritis,scleroderma, and systemic inflammatory response syndrome.

In embodiments, the inflammatory disease or disorder is selected fromthe group consisting of oral mucositis, stomatitis, chelitis, glossitis,and Sjogren's syndrome.

In embodiments, the inflammatory disease or disorder is osteoarthritisor rheumatoid arthritis.

In embodiments, the inflammatory disease or disorder is adipose tissueinflammation.

In embodiments, the inflammatory disease or disorder is vascularinflammation.

In embodiments, the inflammatory disease or disorder is heart ischemia.

In embodiments, the inflammatory disease or disorder is endometriosis.

In embodiments, the inflammatory disease or disorder is oral mucositis.

In embodiments, the inflammatory disease or disorder is a disease ordisorder of the ocular system. In embodiments, the disease or disorderof the ocular system is selected from the group consisting ofinflammatory diseases of the eye, dry eye syndrome, macular edema andretinopathy. In embodiments, the method is a method for promotingcorneal wound healing.

In embodiments, the method is a method for treating dry eye. Dry eyedisease or syndrome is a multifactorial disorder of the tears and ocularsurface characterized by symptoms of dryness and irritation.Inflammation is an important component in the development andpropagation of dry eye (Stevenson et al., Arch. Ophthalmol., 2012,130(1),90-100; Rashid et al., Arch. Ophthalmol, 2008, 126(2),219-225).

The term“dry eye” refers to inadequate tear production and/or abnormaltear composition. Causes of dry eye disease as defined herein includebut are not limited to the following: idiopathic, congenital alacrima,xerophthalmia, lacrimal gland ablation, and sensory denervation;collagen vascular diseases, including rheumatoid arthritis, Wegener'sgranulomatosis, and systemic lupus erythematosus; Sjogren's syndrome andautoimmune diseases associated with Sjogren's syndrome; abnormalities ofthe lipid tear layer caused by blepharitis or rosacea; abnormalities ofthe mucin tear layer caused by vitamin A deficiency; trachoma,diphtheric keratoconjunctivitis; mucocutaneous disorders; aging;menopause; and diabetes. Further, the term “dry eye” includes dry eyeafter anterior ophthalmic operation such as cataract operation andrefractive surgery and that accompanied with allergic conjunctivitis Dryeye symptoms as defined herein may also be provoked by othercircumstances, including, but not limited to, the following: prolongedvisual tasking; working on a computer; being in a dry environment;ocular irritation; contact lenses, LASIK and other refractive surgeries;fatigue; and medications such as isotretinoin, sedatives, diuretics,tricyclic antidepressants, antihypertensives, oral contraceptives,antihistamines, nasal decongestants, beta-blockers, phenothiazines,atropine, and pain relieving opiates such as morphine.

In embodiments, the method further comprises administering a compounddescribed herein with an anti-inflammatory agent. In embodiments, thecompound and the anti-inflammatory agent are contained in the samedosage form.

Metabolic Diseases and Disorders

In embodiments, the present disclosure provides a method for treating ametabolic disease or disorder in a subject in need thereof byadministering to the subject an effective amount of a compound of anyone of Formulas I-V, or mixtures thereof, or a composition comprisingsame. In embodiments, the subject is a human and the compound is acompound of Formula I or IV.

In embodiments, the metabolic disease or disorder is abnormal glucosemetabolism manifesting in diabetes, including type 2 diabetes, orpre-diabetes, insulin resistance, abnormal lipid metabolism manifestingas hypertriglyceridemia, i.e., elevated triglycerides, mixeddyslipidemia, hypercholesterolemia, fatty liver, and combined abnormalglucose and lipid metabolism manifesting in obesity; or a dyslipidemicdisorder selected from hypertriglyceridemia, hypercholesterolemia andmixed dyslipidemias.

In embodiments, the metabolic disease or disorder is insulin resistance,mixed dyslipidemia, nonalcoholic steatohepatitis (NASH), type 2diabetes, primary biliary syndrome, and primary schlerosing cholangitis.

In embodiments, a compound described here is formulated in a singlesolid dosage form with at least one additional API. In embodiments, theat least one additional API is an antihyperlipidemic agent or ananti-diabetic agent. Antihyperlipidemic agents that may be used includeHMG CoA enzyme inhibitors (e.g., statins), cholesterol absorptioninhibitors, and cholesterol esterase transfer protein (CETP) inhibitors.In embodiments, the antihyperlipidemic agent is selected from a statin,a cholesterol absorption inhibitor, a CETP inhibitor, andpharmaceutically-acceptable salts and prodrugs of any of the foregoing.The pharmaceutically acceptable salt may be selected from the groupconsisting of a propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephathalate, sulfonate, xylenesulfonate, phenyl acetate,phenylpropionate, phenylbutyrate, citrate, lactate, p-hydroxybutyrate,glycolate, tartrate, methanesulfonate, propanesulfonates,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, hippurate,gluconate, and lactobionate salt.

In embodiments, the antihyperlipidemic agent is a statin. Inembodiments, the statin is selected from the group consisting ofatorvastatin, risuvostatin, simvastatin, pravastatin, andpharmaceutically acceptable salts and prodrugs of any of the foregoing.In embodiments, the statin is present in an amount ranging from 5 mg to100 mg. In one embodiment, the statin is pravastatin.

In embodiments, the antihyperlipidemic agent is a cholesterol absorptioninhibitor. In one embodiment, the cholesterol absorption inhibitor isezetimibe, also known as Zetia.

In embodiments, the antihyperlipidemic agent is a CETP inhibitor. In oneembodiment, the CETP inhibitor is anacetrapib, or a hydrate, or solvatethereof.

Neurological Disorders

In embodiments, the present disclosure provides a method for treating aneurological disorder in a subject in need thereof by administering tothe subject an effective amount of a compound of any one of FormulasI-VI, or mixtures thereof, or a composition comprising same. Inembodiments, the compound is a compound of Formula I or IV. Inembodiments, the neurological diseases and disorders that may be treatedinclude, without limitation, Alzheimer's disease, peripheral nerveinjury, amyotrophic lateral sclerosis, pain, and fibromyalgia. Inembodiments, the neurological disease or disorder is selected frompostoperative delirium, acute postsurgical pain, fibromyalgia,endometriosis, vulvodynia, chronic lower back pain, treatment ormanagement of pain associated with osteoarthritis, diabetic peripheralneuropathy and musculoskeletal injury or trauma.

In embodiments, the amount is effective to treat one or more symptoms ofthe neurological disorder.

In embodiments, the neurological disorder is a psychiatric disorder. Inembodiments, the psychiatric disorder is selected from attention deficithyperactivity disorder (ADHD) and depression. In embodiments, theneurological disease or disorder is postoperative cognitive dysfunction(POCD) or postoperative delirium.

The disclosure also provides methods for treating or managing pain. Inembodiments, the pain is nociceptive pain and the method comprisesadministering to a subject in need of treatment for nociceptive pain apharmaceutical composition comprising an effective amount a compounddescribed here, or mixtures thereof. In embodiments, the methods furthercomprise administering at least one additional API. In embodiments, theadditional API is gabapentin, or a pharmaceutically acceptable salt orprodrug thereof.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with inflammation.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with fibromyalgia.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with endometriosis.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with vulvodynia.

In embodiments, the disclosure also provides methods for treating ormanaging acute postsurgical pain.

In embodiments, the disclosure also provides methods for treating ormanaging chronic lower back pain.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with osteoarthritis.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with diabetic peripheral neuropathy.

In embodiments, the disclosure also provides methods for treating ormanaging pain associated with musculoskeletal injury or trauma.

Pulmonary and Vascular Diseases and Disorders

In embodiments, the present disclosure provides a method for treating apulmonary disorder in a subject in need thereof by administering to thesubject an effective amount of a compound of any one of Formulas I-VI,or mixtures thereof, or a composition comprising same. In embodiments,the subject is human and the compound is a compound of Formula I or IV.

In embodiments, the pulmonary and vascular diseases and disorders thatmay be treated include, without limitation, pulmonary inflammation,bronchopulmonary dysplasia, also referred to as chronic lung disease ofinfancy, cystic fibrosis, allergic airway response, acute lung injury,lung injury, idiopathic pulmonary fibrosis, bacterial pneumonia,cigarette smoke-induced lung inflammation, and vascular inflammation.

In embodiments, the pulmonary disorder is selected from acute lunginjury, bronchopulmonary dysplasia, also referred to as chronic lungdisease of infancy, cystic fibrosis, idiopathic pulmonary fibrosis, lunginjury, and pulmonary inflammation.

In embodiments, the pulmonary disorder is bronchopulmonary dysplasia,also referred to as chronic lung disease of infancy.

In embodiments, the pulmonary disorder is cystic fibrosis.

In embodiments, the pulmonary disorder is idiopathic pulmonary fibrosis.

Non-Pharmaceutical Uses

In one embodiment, the invention provides compositions comprising acompound described herein, and mixtures of the same, for anon-pharmaceutical use. e.g., for use as a dietary supplement.

In embodiments, the non-pharmaceutical use may comprise administering tothe subject an effective amount of a composition comprising a compounddescribed here, or a mixture of two or more of the compounds describedhere. In embodiments, the effective amount is an amount effective tomaintain, promote, or improve the general health of the subject.

In one embodiment, the composition may be used in a method to counter adietary deficiency or nutritional disorder in a subject. In oneembodiment, the composition may be used in a method for maintaining,promoting, or improving the general health of a subject.

In one embodiment, the method is a method for improving heart health.

In one embodiment, the method is a method for improving joint health.

In one embodiment, the method is a method for improving eye health.

In one embodiment, the method is a method for improving cognitivehealth.

Combination Therapies

In the context of the methods described above, the method may furthercomprise administering a compound described herein as a combinationtherapy, with one or more additional APIs or non-pharmaceutical agentsintended to treat or ameliorate one or more symptoms of the disease ordisorder, or to provide additional non-pharmaceutical benefits asdescribed above. In embodiments, a compound described herein may beadministered together with the at least one additional API ornon-pharmaceutical agent, or separately from the additional API ornon-pharmaceutical agent. Where delivery is together, a composition ofthe invention may be delivered in the same dosage form as the additionalAPI or non-pharmaceutical agent, or in a different dosage form. One ofthe advantages of the present invention, as discussed above, is the easeof formulating the compositions described herein with additional APIs ornon-pharmaceutical agents and excipients in a single solid dosage formdue to their form as a free flowing powder that is chemically andphysically stable (as opposed to the relatively unstable oily liquidform of free SPMs and their esters).

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

The structures of exemplary compounds of Formulas I and IV are shown inTable 5 below.

TABLE 5 Structures of Representative Compounds of Formulas I and IV Cmpd# Name Structure  1 RvE1- MgLys

 2 RvE1- CaLys

 3 RvE1- ZnLys

 4 RvE1- LysLys

 5 RvE1- LysLys (linear)

 6 AT(18S)- RvE1- MgLys

 7 AT(18S)- RvE1- CaLys

 8 AT(18S)- RvE1- ZnLys

 9 AT(18S)- RvE1- LysLys

10 AT(18S)- RvE1- LysLys (linear)

11 LxA4- MgLys

12 LxA4- CaLys

13 LxA4- ZnLys

14 LxA4- LysLys

15 LxA4- LysLys (linear)

16 AT(15e)- LxA4- MgLys

17 AT(15e)- LxA4- CaLys

18 AT(15e)- LxA4- ZnLys

19 AT(15e)- LxA4- LysLys

20 AT(15e)- LxA4- LysLys (linear)

21 RvD1- MgLys

22 RvD1- CaLys

23 RvD1- ZnLys

24 RvD1- LysLys

25 RvD1- LysLys (linear)

26 AT(17e)- RvD1- MgLys

27 AT(17e)- RvD1- CaLys

28 AT(17e)- RvD1- ZnLys

29 AT(17e)- RvD1- LysLys

30 AT(17e)- RvD1- LysLys (linear)

31 RvD2- MgLys

32 RvD2- CaLys

33 RvD2- ZnLys

34 RvD2- LysLys

35 RvD2- LysLys (linear)

36 PDX- MgLys

37 PDX- CaLys

38 PDX- ZnLys

39 PDX- LysLys

40 PDX- LysLys (linear)

Cmpd # Name Structure  1 RvE1- MgLys

 2 RvE1- CaLys

 3 RvE1- ZnLys

 4 RvE1- LysLys

 5 RvE1- LysLys (linear)

 6 AT(18S)- RvE1- MgLys

 7 AT(18S)- RvE1- CaLys

 8 AT(18S)- RvE1- ZnLys

 9 AT(18S)- RvE1- LysLys

10 AT(18S)- RvE1- LysLys (linear)

11 LxA4- MgLys

12 LxA4- CaLys

13 LxA4- ZnLys

14 LxA4- LysLys

15 LxA4- LysLys (linear)

16 AT(15e)- LxA4- MgLys

17 AT(15e)- LxA4- CaLys

18 AT(15e)- LxA4- ZnLys

19 AT(15e)- LxA4- LysLys

20 AT(15e)- LxA4- LysLys (linear)

21 RvD1- MgLys

22 RvD1- CaLys

23 RvD1- ZnLys

24 RvD1- LysLys

25 RvD1- LysLys (linear)

26 AT(17e)- RvD1- MgLys

27 AT(17e)- RvD1- CaLys

28 AT(17e)- RvD1- ZnLys

29 AT(17e)- RvD1- LysLys

30 AT(17e)- RvD1- LysLys (linear)

31 RvD2- MgLys

32 RvD2- CaLys

33 RvD2- ZnLys

34 RvD2- LysLys

35 RvD2- LysLys (linear)

36 PDX- MgLys

37 PDX- CaLys

38 PDX- ZnLys

39 PDX- LysLys

40 PDX- LysLys (linear)

EXAMPLES

Chemical synthesis of the peptide-metal salt component of the compoundsdescribed here using other divalent metal cations than those exemplifiedbelow can be accomplished by adapting the methods described here usingtechniques known in the art. For example, as described in U.S. Pat. No.5,061,815, which is incorporated herein by reference in its entirety. Inaddition, the skilled person would appreciate that different SPMmolecules from those exemplified below may be combined with themetal-dipeptide and dipeptide scaffolds described below in the samemanner.

Provided here are exemplary methods of synthesizing representative SPMmolecules, for example RvE1, AT-RvD1, RvD2, PDX, and LXA4. These areintended to be non-limiting, as the skilled person may employ analternate method for obtaining the SPM component of a compound describedhere. For example, methods of synthesis are described in Li et al.,Beilstein J. Org. Chem. 2013, 9, 2762-2766 and Vik et al., Bioorganicand Med. Chem. Let 2017. In addition, one or more SPMs may be availablefor purchase from a vendor such as Caymen Chemical Co. (Ann Arbor,Mich.).

Example 1: Synthesis of RvE1(5S,6Z,8E,10E,12R,14Z,16E,18R)-5,12,18-trihydroxyicosa-6,8,10,14,16-pentaenoicacid)

Step 1: isopropyl(5S,8E,10E,12R,16E,18R)-5,12,18-trihydroxyicosa-8,10,16-trien-6,14-diynoate

A degassed solution of isopropyl(5S,8E,10E,12R)-5,12-dihydroxypentadeca-8,10-dien-6,14-diynoate (3.972g, 13.05 mmol) in benzene (50 mL) was added to a degassed solution of(RE)-1-iodopent-1-en-3-ol (3.62 g, 17.07 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.464 g, 0.661 mmol),tetrakis(triphenylphosphine)palladium(0) (0.482 g, 0.417 mmol), andcopper(I) iodide (0.255 g, 1.34 mmol) in benzene (25 mL). The mixturewas degassed and purged with nitrogen (2×), piperidine (6.5 mL, 65.8mmol) was added, the solution was degassed and purged with nitrogen, andthe mixture stirred at room temperature under nitrogen atmosphere. After2 hr, TLC (50% EtOAc/hexane, permanganate stain) showed consumption ofthe limiting reagent. The reaction was diluted with EtOAc (240 mL) andwashed with saturated aqueous ammonium chloride (2×100 mL) and brine(100 mL). The organic solution was dried (Na₂SO₄) and concentrated invacuo. The crude viscous dark amber oil/red solid was purified by flashchromatography (0.75 L silica gel, 40% EtOAc/hexane then 50% onceproduct started to elute) to afford 4.22 g (83%) of isopropyl(5S,8E,10E,12R,16E,18R)-5,12,18-trihydroxyicosa-8,10,16-trien-6,14-diynoateas a viscous amber oil. 1H NMR (400 MHz, Chloroform-d) δ 6.56 (dd,J=15.5, 10.9 Hz, 1H), 6.33 (dd, J=14.9, 11.1 Hz, 1H), 6.08 (dd, J=15.9,6.1 Hz, 1H), 5.85 (dd, J=15.2, 5.9 Hz, 1H), 5.73-5.59 (m, 2H), 5.00(hept, J=6.2 Hz, 1H), 4.51 (q, J=4.8, 3.7 Hz, 1H), 4.35 (q, J=6.1 Hz,1H), 4.13-4.01 (m, 1H), 2.68-2.50 (m, 2H), 2.39-2.28 (m, 2H), 1.86-1.68(m, 4H), 1.56 (p, J=7.4 Hz, 2H), 1.22 (d, J=6.3 Hz, 6H), 0.92 (t, J=7.4Hz, 3H).

Step 2: isopropyl(5S,6Z,8E,10E,12R,14Z,16E,18R)-5,12,18-trihydroxyicosa-6,8,10,14,16-pentaenoate

Zinc dust (208 g, 3.2 mol) and water (1.2 L) were added to a flask anddegassed by passing a stream of nitrogen through the solution for 15min. Copper(II) acetate monohydrate (20.9 g, 105 mmol) was added and thedegassing continued for 15 min. Silver nitrate (21 g, 123 mmol) wasadded and the mixture stirred for 30 min under continued nitrogendegassing. The mixture was filtered (#2 filter paper, 18.5 cm Buchnerfunnel) and the remaining solid was washed with water (2×200 mL),methanol (2×200 mL), acetone (2×200 mL) and diethyl ether (2×200 mL).The activated zinc was quickly transferred to a flask containing 1:1methanol/water (1.2 L) and was treated with a solution of isopropyl(5S,8E,10E,12R,16E,18R)-5,12,18-trihydroxyicosa-8,10,16-trien-6,14-diynoate(2.1 g, 5.4 mmol) in methanol (56 mL) and trimethylsilyl chloride (9.3mL, 73 mmol), warmed to 40° C., and stirred overnight under nitrogen.The reaction was monitored by GC-MS and showed 99% conversion after 22hours. The mixture was filtered (250 mL Celite in between two 185 mm #2filter papers in a Buchner funnel) and the filter cake was rinsed withmethanol until no product remained on the cake. The filtrate wasconcentrated in vacuo (water bath temperature <40° C.) until ˜99% of theinitial volume was removed. To the remaining solution was added brine(50 mL), a small amount of sodium chloride, and EtOAc (50 mL). Theorganic layer was collected and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic solution was dried (Na₂SO₄) andconcentrated in vacuo (water bath temperature <30° C.). The crude yellowoil was purified by flash chromatography using a Biotage Isolera (120 gsilica gel, 10-60% EtOAc/hexane, product elutes in 60% EtOAc/hexane) toafford 1.27 g (60%) of isopropyl(5S,6Z,8E,10E,12R,14Z,16E,18R)-5,12,18-trihydroxyicosa-6,8,10,14,16-pentaenoateas a transparent yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 6.49 (ddd,J=15.8, 11.2, 4.5 Hz, 2H), 6.35-6.04 (m, 4H), 5.78 (dd, J=15.2, 6.9 Hz,1H), 5.72 (dd, J=15.2, 6.9 Hz, 1H), 5.44 (ddd, J=16.0, 10.5, 8.1 Hz,2H), 5.00 (hept, J=6.1 Hz, 1H), 4.58 (q, J=6.8, 6.3 Hz, 1H), 4.26 (q,J=6.4 Hz, 1H), 4.15-4.05 (m, 1H), 2.48 (hept, J=7.6 Hz, 2H), 2.30 (t,J=7.0 Hz, 2H), 1.87-1.45 (m, 9H), 1.23 (s, 3H), 1.21 (s, 3H), 0.92 (t,J=7.4 Hz, 3H).

Step 3:(5S,6Z,8E,10E,12R,14Z,16E,18R)-5,12,18-trihydroxyicosa-6,8,10,14,16-pentaenoicacid (RvE1)

A solution of isopropyl(5S,6Z,8E,10E,12R,14Z,16E,18R)-5,12,18-trihydroxyicosa-6,8,10,14,16-pentaenoate(2.51 g, 6.08 mmol) in THF (37 mL) was treated with 1M LiOH solution (26mL, 26 mmol). After stirring for 2 hr at room temperature TLC (EtOAc)showed completion. The reaction mixture was diluted with EtOAc (250 mL)and acidified to pH 7-8 with pH 7 0.2M sodium phosphate buffer (28 mL).The layers were separated and sodium chloride was added to the aqueouslayer until it was saturated. The aqueous layer was washed with EtOAcuntil no product remained. The combined organic solution was washed withbrine, dried (Na₂SO₄), tocopherol (1 drop) was added, and concentratedin vacuo. The crude viscous amber oil was dissolved in 15% MeOH/DCM andpurified by flash chromatography (125 mL silica gel, 0-20% MeOH/DCM) toafford 1.38 g (65%) of(5S,6Z,8E,10E,12R,14Z,16E,18R)-5,12,18-trihydroxyicosa-6,8,10,14,16-pentaenoicacid as an amber oil. 1H NMR (400 MHz, Methanol-d4) δ 6.52 (ddd, J=19.6,14.7, 11.3 Hz, 2H), 6.36-6.18 (m, 2H), 6.07 (t, J=11.0 Hz, 2H), 5.75(dd, J=14.6, 6.5 Hz, 1H), 5.65 (dd, J=15.2, 6.7 Hz, 1H), 5.44 (dt,J=10.3, 7.5 Hz, 1H), 5.41-5.31 (m, 1H), 4.56 (q, J=7.0 Hz, 1H), 4.16 (q,J=6.5 Hz, 1H), 4.00 (q, J=6.5 Hz, 1H), 2.44 (hept, J=7.3 Hz, 2H), 2.30(t, J=6.9 Hz, 2H), 1.73-1.40 (m, 6H), 0.90 (t, J=7.4 Hz, 3H).

Example 2: Synthesis of RvE1 (L,L)-Lysyllysine Salt

A solution of RvE1 (38.1 mg, 0.109 mmol) in methanol (0.75 mL) andtocopherol (1.7 mg pre-dissolved in 0.2 mL of ethyl acetate) was treatedwith L-lysyl-L-lysine (30 mg, 0.109 mmol) and the mixture stirred for 20min at 50° C. The solution cooled slightly, was concentrated in vacuo,and then placed in a vacuum oven at room temperature for 3 hr to afford63 mg (93%) of RvE1 (L,L)-lysyllysine salt as a very pale orange crispfoam. 1H NMR (400 MHz, Methanol-d4) δ 6.62-6.44 (m, 2H), 6.37-6.16 (m,2H), 6.07 (q, J=10.7 Hz, 2H), 5.74 (dd, J=14.8, 6.6 Hz, 1H), 5.65 (dd,J=15.2, 6.7 Hz, 1H), 5.45 (dt, J=10.8, 7.7 Hz, 1H), 5.42-5.30 (m, 1H),4.57 (q, J=7.1 Hz, 1H), 4.26 (dd, J=7.9, 5.2 Hz, 1H), 4.16 (q, J=6.5 Hz,1H), 4.01 (q, J=6.6 Hz, 1H), 2.90 (t, J=7.2 Hz, 4H), 2.43 (tt, J=14.5,7.8 Hz, 2H), 2.18 (t, J=6.8 Hz, 2H), 1.87 (td, J=13.4, 7.9 Hz, 2H),1.75-1.40 (m, 16H), 0.91 (t, J=7.4 Hz, 3H).

Example 3: Synthesis of bis RvE1 Mg di-(L)-lysinate Salt

A solution of RvE1 (60.3 mg, 0.172 mmol) in methanol (1 mL) andtocopherol (2.1 mg pre-dissolved in 0.2 mL of ethyl acetate) was treatedwith magnesium lysinate (27.1 mg, 0.086 mmol) and the mixture stirredfor 20 min at 50° C. The solution cooled slightly, was concentrated invacuo, and then placed in a vacuum oven at room temperature for 3 hr toafford 85 mg (97%) of bis(RvE1) magnesium L-lysinate salt as a very paleorange crisp foam. 1H NMR (400 MHz, Acetic Acid-d4) δ 6.61-6.46 (m, 4H),6.33 (dd, J=14.8, 10.6 Hz, 2H), 6.24 (dd, J=14.6, 10.5 Hz, 2H), 6.10(td, J=11.1, 4.1 Hz, 4H), 5.79 (dd, J=14.9, 6.7 Hz, 2H), 5.69 (dd,J=15.2, 6.8 Hz, 2H), 5.45 (dt, J=14.6, 8.9 Hz, 4H), 4.71 (q, J=7.5, 6.9Hz, 2H), 4.30 (q, J=6.5 Hz, 2H), 4.15 (q, J=6.6 Hz, 2H), 4.04 (t, J=6.2Hz, 2H), 3.07 (t, J=7.4 Hz, 4H), 2.50 (ddq, J=28.8, 14.7, 7.0 Hz, 4H),2.39 (t, J=7.1 Hz, 4H), 2.02-1.90 (m, 4H), 1.81-1.46 (m, 20H), 0.89 (t,J=7.4 Hz, 6H).

Example 4: Synthesis of bis RvE1 Ca di-(L)-lysinate Salt

A solution of RvE1 (74.2 mg, 0.212 mmol) in methanol (0.7 mL) andtocopherol (2.6 mg pre-dissolved in 0.2 mL of ethyl acetate) was treatedwith a solution of calcium lysinate (35 mg, 0.106 mmol) in MeOH (0.6 mL)and the mixture stirred for 20 min at 50° C. The solution cooledslightly, was concentrated in vacuo, and then placed in a vacuum oven atroom temperature for 3 hr to afford 104 mg (96%) of bis(RvE1) calciumL-lysinate salt as a pale orange solid. 1H NMR (400 MHz, DeuteriumOxide) δ 6.64 (td, J=11.5, 2.9 Hz, 2H), 6.54 (dd, J=15.3, 11.1 Hz, 2H),6.42-6.29 (m, 4H), 6.20 (t, J=11.0 Hz, 4H), 5.89-5.79 (m, 2H), 5.76 (dd,J=15.3, 7.0 Hz, 2H), 5.57-5.46 (m, 2H), 5.44 (t, J=10.0 Hz, 2H), 4.67(q, J=6.8 Hz, 2H), 4.32 (q, J=6.5 Hz, 2H), 4.13 (q, J=6.7 Hz, 2H), 3.59(t, J=6.1 Hz, 2H), 3.06-2.95 (m, 4H), 2.51 (t, J=7.2 Hz, 4H), 2.20 (t,J=7.0 Hz, 4H), 1.81 (dtd, J=9.1, 6.4, 2.7 Hz, 4H), 1.75-1.37 (m, 24H),0.88 (t, J=7.4 Hz, 6H).

Example 5: Synthesis of AT-RvD1(4Z,7S,8R,9E,11E,13Z,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,13,15,19-hexaenoicacid (17-epi-RvD1)

Step 1: methyl(Z)-6-((4S,5R)-5-((R,1E,3E,7E,11Z)-9-hydroxytetradeca-1,3,7,11-tetraen-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)hex-4-enoate

A mixture of (R,1E,5Z)-1-iodoocta-1,5-dien-3-ol (1.18 g, 4.03 mmol) andmethyl (Z)-6-((4S,5R)-5-((1E,3E)-hexa-1,3-dien-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)hex-4-enoate (1.13 g 3.71mmol) was azeotropically dried with anhydrous acetonitrile (25 mL). Themixture was dissolved in anhydrous acetonitrile (43 mL), degassed andpurged with nitrogen (2×), treated withbis(triphenylphosphine)palladium(II)chloride (388.3 mg, 0.553 mmol) andcopper iodide (516.9 mg, 2.71 mol), degassed, cooled to 0° C., treatedwith triethylamine (2.7 mL, 19.4 mmol), stirred for 2 hr at 0° C.,warmed to room temperature, and stirred overnight. After 18.5 hr, TLC(30% EtOAc/hexane) showed the limiting reagent was consumed, and pH 70.2M sodium phosphate buffer (20 mL) and EtOAc (80 mL) were added to theflask. The layers were separated and the combined organic solution waswashed with water (until Cu was gone), brine (50 mL), dried (Na₂SO₄),and concentrated in vacuo. The crude oil was purified by flashchromatography (140 mL silica gel, 20-30% EtOAc/hexane) to afford 0.46 g(29%) of methyl(Z)-6-((4S,5R)-5-((R,1E,3E,7E,11Z)-9-hydroxytetradeca-1,3,7,11-tetraen-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)hex-4-enoate.1H NMR (400 MHz, Chloroform-d) δ 6.59 (dd, J=15.4, 11.0 Hz, 1H), 6.42(dd, J=14.6, 14.1 Hz, 1H), 6.33 (m, 1H), 6.16 (dd, J=15.9, 5.6 Hz, 1H),5.88 (m, 1H), 5.75 (m, 1H), 5.67-5.54 (m, 1H), 5.44 (p, J=6.5, 5.9 Hz,2H), 5.41-5.28 (m, 1H), 4.59 (t, J=7.0 Hz, 1H), 4.34-4.14 (m, 2H), 3.67(s, 3H), 2.40-2.30 (m, 6H), 2.30-2.21 (m, 1H), 2.21-2.12 (m, 1H),2.12-2.01 (m, 2H), 1.70 (d, J=4.0 Hz, 1H), 1.49 (s, 3H), 1.36 (s, 3H),0.97 (t, J=7.6 Hz, 3H).

Step 2: methyl(4Z,7S,8R,9E,11E,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,15,19-pentaen-13-ynoate

A solution of methyl(Z)-6-((4S,5R)-5-((R,1E,3E,7E,11Z)-9-hydroxtetradeca-1,3,7,11-tetraen-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)hex-4-enoate(0.38 g, 0.883 mmol) in methanol (31 mL) was treated with 1M HCl (8 mL,8 mmol) and stirred at room temperature. After 4 hr TLC (50%EtOAc/hexane, permanganate stain) showed completion. The reaction wasquenched with saturated aqueous sodium bicarbonate (40 mL) and thenextracted with EtOAc (100 mL). The combined organic solution was washedwith water (60 mL), brine (30 mL), dried (Na₂SO₄), and concentrated invacuo. The crude product was purified by flash chromatography using theBiotage Isolera (25 g silica, 45-90% EtOAc/hexane) to afford 0.34 g(99%) of methyl(4Z,7S,8R,9E,1E,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,15,19-pentaen-13-ynoateas a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 6.60 (dd, J=15.4, 10.9Hz, 1H), 6.38 (dd, J=15.4, 10.8 Hz, 1H), 6.16 (dd, J=15.8, 5.6 Hz, 1H),5.93-5.82 (m, 2H), 5.75 (dd, J=15.4, 2.0 Hz, 1H), 5.66-5.54 (m, 1H),5.48 (td, J=4.8, 2.3 Hz, 2H), 5.40-5.28 (m, 1H), 4.23 (m, 2H), 3.72 (dq,J=8.2, 4.0 Hz, 1H), 3.67 (s, 3H), 2.53 (d, J=4.0 Hz, 1H), 2.48-2.15 (m,9H), 2.05 (d, J=10.0 Hz, 2H), 1.71 (d, J=4.3 Hz, 1H), 0.97 (t, J=7.5 Hz,3H).

Step 3: methyl(4Z,7S,8R,9E,11E,13Z,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,13,15,19-hexaenoate

Zinc dust (22.3 g, 341 mmol) and water (250 mL) were added to a flaskand degassed by passing a stream of nitrogen through the solution for 15min. Copper(II) acetate monohydrate (2.24 g, 11.2 mmol) was added andthe degassing continued for 15 min. Silver nitrate (2.24 g, 13.2 mmol)was added and the mixture stirred for 30 min under continued nitrogendegassing. The mixture was filtered through a medium fritted Buchnerfunnel and the remaining solid was washed with water (2×50 mL), methanol(2×50 mL), acetone (2×50 mL) and diethyl ether (2×50 mL). The zincmixture was quickly transferred to a flask containing 1:1 methanol/water(220 mL) and was treated with a solution of methyl(4Z,7S,8R,9E,1E,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,15,19-pentaen-13-ynoate(350 mg, 0.901 mmol) in methanol (325 mL), trimethylsilyl chloride (1.56mL, 12.2 mmol), and stirred overnight. The reaction was monitored byGCMS and showed 100% conversion after 22 hours. The mixture was filteredthrough a pad of Celite (100 mL, filter cake was rinsed with methanoluntil all product had passed through the Celite), and the filtrate wasconcentrated in vacuo (water bath temperature <30° C.) until ˜80% of theinitial volume was removed. To the remaining solution was added brine(50 mL) and EtOAc (80 mL). The organic layer was collected and theaqueous layer was extracted with EtOAc (30 mL). The combined organicsolution was washed with brine (20 mL), dried (Na₂SO₄), and concentratedin vacuo (water bath temperature <30° C.). The crude product waspurified by flash chromatography (40 mL silica gel, 50% EtOAc/hexane) toafford 288 mg (82%) of methyl(4Z,7S,8R,9E,11E,13Z,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,13,15,19-hexaenoateas a glassy, pale yellow solid. Note: One drop of (+)-α-tocopherol wasadded to the purified product before the solvent was removed. 1H NMR(400 MHz, Chloroform-d) δ 6.79-6.65 (m, 2H), 6.40 (dd, J=15.1, 10.8 Hz,1H), 6.27 (dd, J=14.6, 10.8 Hz, 1H), 6.08-5.96 (m, 2H), 5.80 (ddd,J=15.1, 12.6, 6.5 Hz, 2H), 5.64-5.54 (m, 1H), 5.49 (t, J=5.0 Hz, 2H),5.41-5.31 (m, 1H), 4.30-4.19 (m, 2H), 3.71 (dt, J=7.9, 4.0 Hz, 1H), 3.66(s, 3H), 2.51-2.15 (m, 10H), 2.14-2.01 (m, 2H), 1.75 (s, 1H), 0.97 (t,J=7.5 Hz, 3H).

Step 4:(4Z,7S,8R,9E,11E,13Z,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,13,15,19-hexaenoicacid (17-epi-RvD1)

A cooled (3° C.) solution of methyl(4Z,7S,8R,9E,11E,13Z,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,13,15,19-hexaenoate(246 mg, 0.630 mmol) in THF (13 mL) was treated with 1M aqueous LiOHsolution (3.8 mL, 3.8 mmol). After stirring for 22 hr at 3° C. TLC(EtOAc, CAM stain) showed completion. The reaction mixture was dilutedwith EtOAc (60 mL) and acidified to pH 7-8 with pH 7 0.2M sodiumphosphate buffer (˜17 mL). The layers were separated and the aqueouslayer was washed with EtOAc until product was no longer in aqueous layer(6×10 mL). The combined organic solution was washed with water (25 mL),brine (15 mL), dried (Na₂SO₄), tocopherol (4.2 mg) was added, andconcentrated in vacuo to afford 207 mg (87%) of(4Z,7S,8R,9E,11E,13Z,15E,17R,19Z)-7,8,17-trihydroxydocosa-4,9,11,13,15,19-hexaenoicacid (17-epi-RvD1) as a translucent yellow oil. 1H NMR (400 MHz,Chloroform-d) δ 6.69 (m, 1H), 6.42-6.27 (m, 1H), 6.29-6.16 (m, 1H),6.04-5.92 (m, 2H), 5.77 (m, 2H), 5.59-5.40 (m, 3H), 5.38-5.27 (m, 1H),4.28-4.07 (m, 2H), 3.74-3.61 (m, 1H), 2.47-2.12 (m, 8H), 2.05 (m, 2H),1.44-1.36 (m, 1H), 1.34-1.15 (m, 2H), 1.01-0.88 (m, 3H), 0.88-0.76 (m,1H).

Example 6: Synthesis of AT-RvD1 (L,L)-Lysyllysine Salt

A solution of 17-epi-RvD1 (27.4 mg, 72.8 μmol) in methanol (0.5 mL) andtocopherol (0.9 mg pre-dissolved in 0.2 mL of ethyl acetate) was treatedwith L-lysyl-L-lysine (19.9 mg, 72.5 μmol) and the mixture stirred for20 min at 50 degrees C. The solution cooled slightly, was concentratedin vacuo, and then placed in a vacuum oven at room temperature for 3 hrto afford 47 mg (100%) of 17-epi-RvD1 (L,L)-Lysyllysine salt as a paleorange crisp foam. 1H NMR (400 MHz, Methanol-d4) δ 6.80-6.68 (m, 2H),6.40 (dd, J=14.8, 11.0 Hz, 1H), 6.29 (dd, J=14.5, 10.8 Hz, 1H), 6.00 (p,J=10.8 Hz, 2H), 5.87 (dd, J=15.0, 6.8 Hz, 1H), 5.73 (dd, J=15.1, 6.5 Hz,1H), 5.57-5.42 (m, 3H), 5.43-5.32 (m, 1H), 4.26 (dd, J=7.8, 5.3 Hz, 1H),4.17 (q, J=6.8 Hz, 1H), 4.02 (t, J=6.1 Hz, 1H), 3.58-3.49 (m, 1H),3.43-3.35 (m, 1H), 2.91 (t, J=7.4 Hz, 4H), 2.40-2.15 (m, 8H), 2.06 (p,J=8.1, 7.7 Hz, 2H), 1.86 (dt, J=13.2, 6.5 Hz, 2H), 1.75-1.58 (m, 6H),1.45 (dq, J=16.5, 9.0, 8.0 Hz, 4H), 0.96 (t, J=7.5 Hz, 3H).

Example 7: Synthesis of bis AT-RvD1 Mg di-(L)-lysinate Salt

A solution of 17-epi-RvD1 (35.9 mg, 95.4 μmol) in methanol (0.5 mL) andtocopherol (1.3 mg pre-dissolved in 0.2 mL of ethyl acetate) was treatedwith magnesium L-lysinate (15 mg, 47.7 μmol) and the mixture stirred for20 min at 50° C. The solution cooled slightly, was concentrated invacuo, and then placed in a vacuum oven at room temperature for 3 hr toafford 51 mg (100%) of bis(l 7-epi-RvD1) magnesium L-lysinate salt as aglassy orange solid. 1H NMR (400 MHz, Acetic Acid-d4) δ 6.81-6.69 (m,4H), 6.41 (dd, J=15.2, 10.8 Hz, 2H), 6.28 (dd, J=14.6, 10.7 Hz, 2H),6.09-5.94 (m, 4H), 5.86 (dd, J=15.1, 7.2 Hz, 2H), 5.77 (dd, J=15.1, 6.6Hz, 2H), 5.49 (m, 6H), 5.36 (dt, J=11.7, 7.5 Hz, 2H), 4.35-4.23 (m, 4H),4.08-4.00 (m, 2H), 3.86-3.77 (m, 2H), 3.13-3.02 (m, 4H), 2.45-2.25 (m,16H), 2.09-1.91 (m, 8H), 1.75 (dt, J=14.4, 7.4 Hz, 4H), 1.58 (m, 4H),0.94 (t, J=7.5 Hz, 6H).

Example 8: Synthesis of RvD2(4Z,7S,8E,10Z,12E,14E,16R,17S,19Z)-7,16,17-trihydroxydocosa-4,8,10,12,14,19-hexaenoicacid)

Step 1: (S,4Z,8E,12E,14E)-methyl15-((4R,5S,)-2,2-dimethyl-5-((Z)-pent-2-en-1-yl)-1,3-dioxolan-4-yl)-7-hydroxypentadeca-4,8,12,14-tetraen-10-ynoate

A mixture of(4R,5S)-4-((1E,3E)-4-iodobuta-1,3-dien-1-yl)-2,2-dimethyl-5-((Z)-pent-2-en-1-yl)-1,3-dioxolane(1.68 g, 4.83 mmol) andmethyl-(S,4Z,8E)-7-hydroxyundeca-4,8-dien-10-ynoate (0.919 g, 4.41 mmol)was azeotropically dried with anhydrous acetonitrile (3×5 mL). Themixture was dissolved in anhydrous acetonitrile (50 mL), degassed undervacuum and purged with nitrogen (2×), treated withbis(triphenylphosphine)palladium(II)chloride (0.318 g, 0.453 mmol) andcopper iodide (0.315 g, 1.65 mmol), degassed, cooled to 0° C., treatedwith triethylamine (3.05 mL, 21.9 mmol), stirred for 2 hr at 0° C., andwarmed to room temperature overnight. After 18 hr, TLC (20%EtOAc/hexane) showed the reaction was complete and pH 7 0.2M sodiumphosphate buffer (75 mL) was added to the flask. The layers wereseparated and the aqueous layer washed with EtOAc (150 mL). The combinedorganic solution was washed with water (2×75 mL), brine (50 mL), dried(Na₂SO₄), and concentrated in vacuo. The crude oil was purified by flashchromatography (30% EtOAc/hexane) to afford 1.48 g (79%) of(S,4Z,8E,12E,14E)-methyl15-((4R,5S,)-2,2-dimethyl-5-((Z)-pent-2-en-1-yl)-1,3-dioxolan-4-yl)-7-hydroxypentadeca-4,8,12,14-tetraen-10-ynoateas a brown oil. 1H NMR (400 MHz, Chloroform-d) δ 6.59 (dd, J=15.4, 10.9Hz, 1H), 6.32 (dd, J=15.0, 10.9 Hz, 1H), 6.17 (dd, J=15.8, 5.5 Hz, 1H),5.90 (d, J=15.8 Hz, 1H), 5.81-5.70 (m, 2H), 5.48 (m, 3H), 5.31 (m, 1H),4.63-4.54 (m, 1H), 4.26 (m, 1H), 4.23-4.13 (m, 1H), 3.67 (s, 3H),2.43-2.33 (m, 6H), 2.27 (dt, J=14.1, 7.2 Hz, 1H), 2.20-2.09 (m, 1H),2.03 (m, 2H), 1.50 (s, 3H), 1.37 (s, 3H), 0.96 (t, J=7.5 Hz, 3H).

Step 2: (4Z,7S,8E,12E,14E,16R,17S,19Z)-methyl7,16,17-trihydroxydocosa-4,8,12,14,19-pentaen-10-ynoate

A solution of (S,4Z,8E,12E,14E)-methyl15-((4R,5S,)-2,2-dimethyl-5-((Z)-pent-2-en-1-yl)-1,3-dioxolan-4-yl)-7-hydroxypentadeca-4,8,12,14-tetraen-10-ynoate(1.48 g, 3.45 mmol) in methanol (75 mL) was treated with 1M HCl (19 mL,18.9 mmol). After stirring for 2 hr TLC (50% EtOAc/hexane, permanganatestain) showed the reaction was complete. The reaction was quenched withsat. aq. NaHCO₃ (60 mL) and extracted with EtOAc (2×150 mL). The organicsolution was washed with water (100 mL), dried (Na₂SO₄), treated withone drop of (+)-α-tocopherol, and concentrated in vacuo. The crudeproduct was purified by flash chromatography (50% EtOAc/hexane) toafford 1.03 g (77%) of (4Z,7S,8E,12E,14E,16R,17S,19Z)-methyl7,16,17-trihydroxydocosa-4,8,12,14,19-pentaen-10-ynoate. 1H NMR (400MHz, Chloroform-d) δ 6.60 (dd, J=15.4, 10.9 Hz, 1H), 6.37 (dd, J=15.2,11.0 Hz, 1H), 6.17 (dd, J=15.8, 5.5 Hz, 1H), 5.95-5.81 (m, 2H), 5.75 (d,J=14.1 Hz, 1H), 5.64-5.48 (m, 2H), 5.51-5.40 (m, 1H), 5.37 (m, 1H),4.31-4.20 (m, 2H), 3.73 (dt, J=8.6, 4.3 Hz, 1H), 3.67 (s, 3H), 2.44-2.34(m, 6H), 2.29 (dt, J=16.1, 8.2 Hz, 1H), 2.21-2.12 (m, 1H), 2.10-1.98 (m,2H), 0.97 (t, J=7.5 Hz, 3H).

Step 3: (4Z,7S,8E,10Z,12E,14E,16R,17S,19Z)-methyl7,16,17-trihydroxydocosa-4,8,10,12,14,19-hexaenoate

Zinc dust (63.68 g, 973.6 mmol) and water (750 mL) were added tO a flaskand degassed by passing a stream of nitrogen through the solution for 15min. Copper(II) acetate monohydrate (6.35 g, 31.81 mmol) was added andthe degassing continued for another 15 min. Silver nitrate (6.35 g,37.38 mmol) was added and the mixture stirred for 30 min under continuednitrogen degassing. The mixture was filtered through a medium frittedBuchner funnel and the remaining solid was washed with water (2×160 mL),methanol (2×160 mL), acetone (2×160 mL) and ether (2×160 mL). Theactivated zinc was quickly transferred to a flask containing 1:1methanol/water (320 mL) and was treated with a solution of(4Z,7S,8E,12E,14E,16R,17S,19Z)-methyl7,16,17-trihydroxydocosa-4,8,12,14,19-pentaen-10-ynoate (1.03 g, 2.65mmol) in methanol (1 L), trimethylsilyl chloride (4.4 mL, 34.4 mmol),and stirred overnight. The reaction was monitored by GCMS and showed100% conversion after 22 hours. The mixture was filtered through a padof Celite (filter cake was rinsed with methanol), and the filtrate wasconcentrated in vacuo (water bath temperature was kept below 27° C.)until ˜70% of the initial volume was removed. To the remaining solutionwas added water and EtOAc until two layers formed. The organic layer wascollected and the aqueous layer was extracted with EtOAc (2×100 mL). Thecombined organic solution was dried (Na₂SO₄), treated with one drop of(+)-α-tocopherol, and concentrated in vacuo (water bath temperature waskept below 27° C.) to afford 1.27 g (82%) of crude product as a lightyellow oil. 1H NMR (600 MHz, Chloroform-d) δ 6.78-6.67 (m, 1H), 6.37 (m,1H), 6.32-6.22 (m, 1H), 6.03 (m, 1H), 5.84-5.73 (m, 1H), 5.60-5.42 (m,3H), 5.40-5.32 (m, 1H), 4.25 (d, J=26.6 Hz, 2H), 3.73 (dq, J=9.1, 4.6Hz, 1H), 3.67 (s, 3H), 2.45-2.32 (m, 6H), 2.32-2.23 (m, 1H), 2.22-2.13(m, 1H), 2.05 (m, 2H), 0.96 (t, J=7.6 Hz, 3H).

Step 4:(4Z,7S,8E,10Z,12E,14E,16R,17S,19Z)-7,16,17-trihydroxydocosa-4,8,10,12,14,19-hexaenoicacid (RvD2)

A cooled (0° C.) solution of (4Z,7S,8E,10Z,12E,14E,16R,17S,19Z)-methyl7,16,17-trihydroxydocosa-4,8,10,12,14,19-hexaenoate (1.03 g, 2.64 mmol)in THF (54 mL) under nitrogen was treated with 1M LiOH solution (16.5mL, 16.5 mmol) and stirred for 1 d at 4° C. The reaction mixture wasdiluted with EtOAc (150 mL) and acidified (pH 7-8) with pH 7 0.2M sodiumphosphate buffer (175 mL). The layers were separated and the aqueoussolution was extracted well with EtOAc (6×75 mL). The combined organicsolution was washed with water, brine, dried (Na₂SO₄), and concentratedin vacuo to afford 0.94 g (75%) of(4Z,7S,8E,10Z,12E,14E,16R,17S,19Z)-7,16,17-trihydroxydocosa-4,8,10,12,14,19-hexaenoicacid (RvD2) as an opaque, yellow oil. 1H NMR (600 MHz, Chloroform-d) δ6.76-6.67 (m, 2H), 6.40 (dd, J=15.2, 10.8 Hz, 1H), 6.26 (dd, J=14.7,10.8 Hz, 1H), 6.06-5.97 (m, 2H), 5.79 (m, 2H), 5.59-5.44 (m, 3H),5.40-5.33 (m, 1H), 4.28 (q, J=5.9 Hz, 1H), 4.24 (dd, J=6.9, 3.6 Hz, 1H),3.73 (dt, J=8.2, 4.2 Hz, 1H), 2.50-2.32 (m, 6H), 2.31-2.23 (m, 1H), 2.18(dt, J=14.8, 5.8 Hz, 1H), 2.05 (m, J=7.1 Hz, 2H), 0.96 (t, J=7.5 Hz,3H).

Example 9: Synthesis of RvD2 (L,L)-Lysyllysine Salt

A 50° C. solution of L,L-lysyllysine (58.9 mg, 0.215 mmol) in methanol(0.5 mL) was treated with a solution of tocopherol (2.8 mg in 0.2 mL ofEtOAc) and a solution of RvD2 (84.5 mg, 0.224 mmol) in methanol (0.5mL). The solution stirred for 20 minutes, cooled slightly, and wasconcentrated in vacuo. The oil was re-suspended in HPLC gradeacetonitrile (˜3 mL), cooled to 0° C., and stirred for 3 hours totriturate the solid. Only a small amount of filterable solid formed andthe suspension was stored at −20° C. overnight. The material wasfiltered and dried overnight in a vacuum oven (ambient temperature) toafford 46 mg (33%) of RvD2 L,L-lysyllysine salt as a light orange solid.1H NMR (400 MHz, Methanol-d4) δ 6.81-6.70 (m, 2H), 6.39 (dd, J=14.7,10.9 Hz, 1H), 6.29 (dd, J=14.4, 10.9 Hz, 1H), 6.08-5.95 (m, 2H), 5.85(dd, J=15.0, 7.1 Hz, 1H), 5.76 (dd, J=15.1, 6.3 Hz, 1H), 5.58-5.36 (m,4H), 4.27 (dd, J=7.8, 5.3 Hz, 1H), 4.18 (q, J=6.3 Hz, 1H), 4.05-3.97 (m,1H), 3.54 (dt, J=8.2, 4.8 Hz, 1H), 3.41 (t, J=6.6 Hz, 1H), 2.92 (t,J=7.4 Hz, 4H), 2.34 (m, 5H), 2.26-2.14 (m, 3H), 2.10-2.05 (m, 2H), 1.87(m, 2H), 1.68 (m, 6H), 1.47 (m, 4H), 0.97 (t, J=7.5 Hz, 3H).

Example 10: Synthesis of bis RvD2 Mg di-(L)-lysinate Salt

A 50° C. solution of magnesium L-lysinate (40 mg, 0.127 mmol) inmethanol (0.5 mL) was treated with a solution of tocopherol (3.1 mg in0.2 mL of EtOAc) and a solution of RvD2 (104.6 mg, 0.278 mmol) inmethanol (0.5 mL). The mixture stirred for 20 minutes, cooled slightly,and was concentrated in vacuo. The foam was re-suspended in HPLC gradeacetonitrile (˜3 mL), stirred for 1.5 hours to triturate the solid,filtered, and dried overnight in a vacuum oven (ambient temperature) toafford 107 mg (79%) of bis(RvD2) magnesium L-lysinate salt as a lightorange solid. 1H NMR (400 MHz, Acetic Acid-d4) δ 6.83-6.69 (m, 4H), 6.41(dd, J=15.1, 10.8 Hz, 2H), 6.29 (dd, J=14.5, 10.8 Hz, 2H), 6.10-5.96 (m,4H), 5.87 (dd, J=15.1, 7.3 Hz, 2H), 5.79 (dd, J=15.1, 6.6 Hz, 2H),5.54-5.34 (m, 8H), 4.33 (q, J=6.3 Hz, 2H), 4.27 (dd, J=7.1, 3.6 Hz, 2H),4.05 (t, J=6.1 Hz, 2H), 3.82 (m, 2H), 3.08 (t, J=7.3 Hz, 4H), 2.39-2.27(m, 16H), 2.10-1.93 (m, 8H), 1.76 (m, 4H), 1.60 (m, 4H), 0.94 (t, J=7.5Hz, 6H).

Example 11: Synthesis of PDX (L,L)-Lysyllysine Salt

A 50° C. solution of L,L-lysyllysine (55.7 mg, 0.203 mmol) in methanol(0.5 mL) was treated with a solution of tocopherol (1.8 mg in 0.2 mL ofEtOAc) and a solution of PDX (80.0 mg, 0.222 mmol) in methanol (0.5 mL).The solution stirred for 20 minutes, cooled slightly, and wasconcentrated in vacuo. The foam was re-suspended in HPLC gradeacetonitrile (˜3 mL), stirred for 3 hours to triturate the solid,filtered, and dried overnight in the vacuum oven (ambient temperature)to afford 52 mg (39%) of PDX L,L-lysyllysine salt as a very sticky,orange solid. 1H NMR (400 MHz, Methanol-d4) δ 6.70 (dd, J=14.6, 9.3 Hz,2H), 6.01-5.89 (m, 2H), 5.71 (ddd, J=14.8, 8.0, 6.4 Hz, 2H), 5.51-5.25(m, 6H), 4.24 (dd, J=7.7, 5.3 Hz, 1H), 4.14 (m, 2H), 3.38 (t, J=6.5 Hz,1H), 2.89 (t, J=7.3 Hz, 4H), 2.82 (t, J=6.4 Hz, 2H), 2.40-2.21 (m, 6H),2.21-2.13 (m, 2H), 2.04 (m, 2H), 1.91-1.78 (m, 2H), 1.66 (m, 6H), 1.45(m, 4H), 0.94 (t, J=7.5 Hz, 3H).

Example 12: Synthesis of bis PDX Mg di-(L)-lysinate salt

A 50° C. solution of magnesium L-lysinate (40.1 mg, 0.127 mmol) inmethanol (0.5 mL) was treated with a solution of tocopherol (2.2 mg in0.2 mL of EtOAc) and a solution of PDX (103.0 mg, 0.286 mmol) inmethanol (0.5 mL). The solution stirred for 20 minutes, cooled slightlyand was concentrated in vacuo. The oil was re-suspended in HPLC gradeacetonitrile (˜3 mL), stirred for 1.5 hr to triturate the solid,filtered, and dried overnight in a vacuum oven (ambient temperature) toafford 68 mg (50%) of bis(PDX) magnesium L-lysinate salt as a slightlytacky orange solid. 1H NMR (400 MHz, Acetic Acid-d4) δ 6.74 (dd, J=15.2,7.8 Hz, 4H), 6.04-5.92 (m, 4H), 5.76 (ddd, J=15.0, 6.4, 3.6 Hz, 4H),5.53-5.29 (m, 12H), 4.30 (dq, J=13.0, 6.4 Hz, 4H), 4.04 (t, J=5.3 Hz,2H), 3.07 (t, J=7.3 Hz, 4H), 2.83 (t, J=5.4 Hz, 4H), 2.53-2.24 (m, 16H),2.10-1.92 (m, 8H), 1.75 (m, 4H), 1.59 (dt, J=15.1, 6.4 Hz, 4H), 0.93 (t,J=7.5 Hz, 6H).

Example 13: Synthesis of LXA4(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoicacid)

Step 1: ethyl4-((4S,5R)-5-((S,1E,3E,7E)-9-hydroxytetradeca-1,3,7-trien-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate

A degassed solution of ethyl4-((4S,5R)-5-((1E,3E)-hexa-1,3-dien-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate(2.28 g, 7.80 mmol) in benzene (10 mL) was added to a degassed solutionof (S,E)-1-iodooct-1-en-3-ol (2.64 g, 10.39 mmol),dichlorobis(triphenylphosphine)palladium(II) (363 mg, 0.517 mmol), andcopper(I) iodide (181 mg, 0.950 mmol) in benzene (34 mL) under argon.Peperidine (3.8 mL, 38.5 mmol) was added, the mixture was degassed andpurged with argon, and stirred at room temperature under argonatmosphere. After 2 hr, TLC (20% EtOAc/hexane, permanganate stain)showed consumption of the limiting reagent. The reaction was dilutedwith EtOAc (125 mL) and washed with saturated aqueous ammonium chloride(2×40 mL) and brine (40 mL). The organic solution was dried (Na₂SO₄) andconcentrated in vacuo. The crude oil was dissolved in 50% EtOAc/hexaneand purified by flash chromatography (700 mL silica gel, 40-50%EtOAc/hexane) to afford 2.84 g (86%) of ethyl4-((4S,5R)-5-((S,1E,3E,7E)-9-hydroxytetradeca-1,3,7-trien-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoateas a light amber oil. 1H NMR (400 MHz, Chloroform-d) δ 6.58 (dd, J=15.5,10.9 Hz, 1H), 6.29 (dd, J=15.2, 10.9 Hz, 1H), 6.14 (dd, J=15.9, 6.2 Hz,1H), 5.84 (dt, J=15.9, 1.8 Hz, 1H), 5.78-5.65 (m, 2H), 4.55 (t, J=7.0Hz, 1H), 4.22-4.06 (m, 4H), 2.32 (td, J=7.4, 2.4 Hz, 2H), 1.79 (ddtd,J=12.6, 10.1, 7.4, 5.4 Hz, 1H), 1.72-1.48 (m, 5H), 1.48 (s, 3H),1.47-1.36 (m, 2H), 1.35 (s, 3H), 1.30 (q, J=3.7, 2.8 Hz, 4H), 1.25 (t,J=7.1 Hz, 3H), 0.94-0.79 (m, 3H).

Step 2: ethyl(5S,6R,7E,9E,13E,15S)-5,6,15-trihydroxyicosa-7,9,13-trien-11-ynoate

A solution of ethyl4-((4S,5R)-5-((S,1E,3E,7E)-9-hydroxytetradeca-1,3,7-trien-5-yn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate(2.84 g, 6.79 mmol) in EtOH (110 mL) was treated with 1M HCl (34 mL, 34mmol) and stirred at room temperature. After 16 hr, TLC (EtOAc,permanganate stain) showed completion. The reaction was quenched withsaturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc(3×40 mL). The combined organic solution was washed with water (100 mL),brine (150 mL), dried (Na₂SO₄), and concentrated in vacuo. The amber oilwas purified by flash chromatography (400 mL silica gel, 50% then 80%EtOAc/hexane) to afford 1.57 g (61%) of ethyl(5S,6R,7E,9E,13E,15S)-5,6,15-trihydroxyicosa-7,9,13-trien-11-ynoate as ayellow oil. 1H NMR (400 MHz, Chloroform-d) δ 6.58 (dd, J=15.4, 10.9 Hz,1H), 6.35 (dd, J=15.3, 10.9 Hz, 1H), 6.15 (dd, J=15.8, 6.1 Hz, 1H), 5.83(dd, J=15.3, 6.9 Hz, 2H), 5.75 (dd, J=15.4, 2.2 Hz, 1H), 4.14 (dtd,J=17.6, 6.9, 3.3 Hz, 4H), 3.70 (dq, J=8.3, 3.7 Hz, 1H), 2.34 (td, J=7.3,2.2 Hz, 2H), 1.83 (ddq, J=13.2, 9.2, 7.0, 6.5 Hz, 1H), 1.75-1.61 (m,1H), 1.59-1.28 (m, 10H), 1.25 (td, J=7.1, 2.3 Hz, 3H), 0.89 (t, J=6.7Hz, 3H).

Step 3: ethyl(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoate

Zinc dust (104.6 g, 1.6 mol) and water (1.2 L) were added to a flask anddegassed by passing a stream of nitrogen through the solution for 15min. Copper(II) acetate monohydrate (10.4 g, 52 mmol) was added and thedegassing continued for 15 min. Silver nitrate (10.3 g, 61 mmol) wasadded and the mixture stirred for 30 min under continued nitrogendegassing. The mixture was filtered (#2 filter paper, Buchner funnel)and the remaining solid was washed with water (2×100 mL), methanol(2×100 mL), acetone (2×100 mL) and diethyl ether (2×100 mL). The zincwas quickly transferred to a flask containing 1:1 methanol/water (840mL) and was treated with a solution of ethyl(5S,6R,7E,9E,13E,15S)-5,6,15-trihydroxyicosa-7,9,13-trien-11-ynoate(1.57 g, 4.15 mmol) in methanol (400 mL) and trimethylsilyl chloride (7mL, 55 mmol). The suspension stirred overnight at room temperature undernitrogen. The reaction was monitored by GC-MS and showed >99% conversionafter 23 hours. The mixture was filtered (100 mL Celite between two 185mm #2 filter papers in a Buchner funnel) and the filter cake was rinsedwith methanol until no product remained on the cake. The filtrate wasconcentrated in vacuo (water bath temperature <35° C.) until ˜99% of theinitial volume was removed. The remaining solution was diluted withEtOAc (50 mL) and brine (30 mL) and a small amount of sodium chloridewas added. The organic layer was collected and the aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic solution was dried(Na₂SO₄) and concentrated in vacuo (water bath temperature <30° C.). Thecrude yellow wax was dissolved in 1:1 DCM/hexane and purified by flashchromatography (300 mL silica gel, 50% EtOAc/hexane then 75% once theproduct started eluting) to afford 1.26 g (80) of ethyl(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoateas a sticky, translucent, yellow wax. 1H NMR (400 MHz, Chloroform-d) δ6.76-6.63 (m, 1H), 6.44-6.19 (m, 4H), 6.10-5.96 (m, 1H), 5.77 (ddd,J=15.6, 9.1, 6.9 Hz, 2H), 4.24-4.17 (m, 1H), 4.12 (qd, J=7.2, 2.7 Hz,3H), 3.70 (s, 1H), 2.40-2.31 (m, 2H), 1.89-1.77 (m, 2H), 1.75-1.64 (m,2H), 1.53-1.19 (m, 14H), 0.94-0.82 (m, 3H).

Step 4:(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoicacid (LxA4)

A cooled (4° C.) solution of ethyl(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoate(1.26 g, 3.31 mmol) in THF (70 mL) was treated with 1M LiOH solution (20mL, 20 mmol). After stirring for 15 hr at 4° C., TLC (EtOAc,permanganate stain) showed completion. The reaction mixture was dilutedwith EtOAc (250 mL) and acidified to pH 7-8 with pH 7 0.2M sodiumphosphate buffer (˜30 mL). The layers were separated and the aqueouslayer was washed with EtOAc until product was no longer in the aqueouslayer. The combined organic solution was washed with water (30 mL),brine (30 mL), dried (Na₂SO₄), tocopherol (5 mg) was added, andconcentrated in vacuo to afford 0.77 g (66%) of(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoicacid as an opaque, light yellow powder. 1H NMR (400 MHz, Methanol-d4) δ6.82-6.64 (m, 2H), 6.38 (dd, J=14.7, 10.6 Hz, 1H), 6.27 (dd, J=14.5,10.8 Hz, 1H), 6.07-5.93 (m, 2H), 5.83 (dd, J=15.0, 6.9 Hz, 1H), 5.71(dd, J=15.0, 6.6 Hz, 1H), 4.12 (q, J=5.9 Hz, 1H), 3.98 (ddd, J=6.6, 5.1,1.1 Hz, 1H), 3.50 (ddd, J=9.3, 5.0, 3.0 Hz, 1H), 2.31 (t, J=7.3 Hz, 2H),1.90-1.76 (m, 1H), 1.70-1.26 (m, 11H), 0.97-0.84 (m, 3H).

Example 14: Synthesis of bis LXA4 Mg di-(L)-lysinate Salt

A solution of LxA4 (84.4.3 mg, 0.240 mmol) in methanol (1.6 mL) andtocopherol (3.3 mg pre-dissolved in 0.2 mL of ethyl acetate) was treatedwith magnesium L-lysinate (37.7 mg, 0.120 mmol) and the mixture stirredfor 20 min at 50° C. The solution cooled slightly, was concentrated invacuo, and then placed in a vacuum oven at room temperature overnight toafford 122 mg (100%) of bis(LxA4) magnesium L-lysinate salt as a verypale orange solid. 1H NMR (400 MHz, Methanol-d4) δ 6.80-6.64 (m, 4H),6.37 (ddd, J=15.1, 10.8, 1.1 Hz, 2H), 6.27 (dd, J=14.5, 10.8 Hz, 2H),6.06-5.92 (m, 4H), 5.83 (dd, J=15.0, 6.9 Hz, 2H), 5.70 (dd, J=15.0, 6.7Hz, 2H), 4.12 (q, J=5.9 Hz, 2H), 3.99 (ddd, J=6.5, 5.0, 1.1 Hz, 2H),3.57-3.47 (m, 4H), 2.91 (dd, J=8.2, 6.8 Hz, 4H), 2.19 (ddd, J=9.0, 7.0,2.3 Hz, 4H), 1.91-1.41 (m, 24H), 1.37-1.26 (m, 12H), 0.94-0.86 (m, 6H).

Example 15: Compounds of Formulas I and IV Show Increased StabilityAgainst Degradation

The stability of selected SPMs and their ionic derivatives based onFormulas I and IV was evaluated. The parent SPM and its solid ionicderivative were place in open test tubes and maintained at roomtemperature between 68-72 F and relative humidity between 20-40% for 6or 8 weeks. Qualitative demonstration of stability was determined usingstandard high pressure liquid chromatography (HPLC) analytic methods.Briefly, HPLC analysis was performed on a PFP column (Poroshell 120,PFP, 4.6×150 mm, 2.7 m, Agilent), mounted on a Gilson HPLC systemequipped with an ELS detector. The mobile phase consisted of a gradientbetween solution A, water, and solution B, acetonitrile, both containing0.1% trifluoroacetic acid. The gradient program was 30-80% with respectto solution B. The flow rate was 0.5 mL/min. The appearance of new HPLCpeaks as compared to the baseline HPLC tracing at the initial time pointis indicative of decomposition products and the lack of stability. Theabsence of such new HPLC peaks the subsequent time points is indicativeof stability.

At the initial time point, RvE1 elutes as a single major peak atretention time (rt) 7 minutes, with minor degradation products at 15 and17.5 minutes (FIG. 1A). Following 8 weeks exposure to the testconditions described above, RvE1 had extensively degraded, as indicatedby the appearance of multiple peaks corresponding to degradationproducts at rt 15 through 25 minutes (FIG. 1B).

In contrast, under the same conditions, RvE1 magnesium (Mg) di-lysinatedid not exhibit any degradation products. At the initial time point,RvE1 Mg di-lysinate elutes as two peaks representing its dissociationinto RvE1 (at rt 7 min.) and lysine (at rt 3 min.) from the RvE1 Mgdi-lysinate salt (compare FIGS. 2A and 2B).

Similarly, the calcium (Ca) di-lysinate salt form of RvE1 exhibited thesame enhanced stability profile observed for the Mg di-lysinate saltform (compare FIG. 3A to 3B). In this example and as was observed forthe Mg di-lysinate salt, at both the initial time point and after 6weeks of exposure to the test conditions, the compound elutes as twopeaks, RvE1 (rt 7 min) and lysine (rt 3 min) relecting dissociation ofthe RvE1 Ca di-lysinate salt. No additional peaks corresponding todegradation products were observed.

A representative compound of Formula I, a lysyl lysine (lys lys) saltform of RvE1, showed the same enhanced stability. Like the compounds ofFormula IV, at the initial time point, RvE1 lys lys elutes as two peaks,RvE1 (rt 7 min) and lysine (rt 3 min) (FIG. 4A). After 8 weeks under thetest conditions described above, these same two peaks are present,without degradation products (FIG. 4B).

In summary, these results show that the free acid form of RvE1experienced significant degradation during 8 weeks of exposure to thetest conditions (compare FIG. 1A to 1B), while representative compoundsof Formulas I and IV having RvE1 as the SPM component showed nodegradation of the SPM under the same conditions for the same or similarperiods of time. These results indicate that compounds of Formulas I andIV can significantly improve the stability of the free acid form of anSPM that is otherwise unstable under the conditions used here.

EQUIVALENTS

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

1-21. (canceled)
 22. A compound of Formula IV:

wherein M is a divalent metal selected from magnesium (Mg²⁺), calcium(Ca²⁺), and zinc (Zn²⁺), A and B are each independently an SPM moleculeselected from the group consisting of RvD1, RvD2, RvE1, PDX, LXA4,AT-RvD1, AT-RvD2, AT-PD1, AT-LXA4, and AT-RvE1, A and B may be the sameor different, either A or B, but not both, may be absent, R¹ and R² areeach independently —(CH₂)₃—Y¹, and —(CH₂)₄—Y², where Y¹ and Y² are eacha basic function selected from a positively charged primary amine, apositively charged secondary amine, a positively charged tertiary amine,and a positively charged guanidine, X¹ and X² are each independently Hor CO—Z and Z is a peptide comprising 1 to 5 amino acids.
 23. Thecompound of claim 22, wherein M is selected from magnesium (Mg²⁺) orcalcium (Ca²⁺).
 24. The compound of claim 22, wherein R¹ and R² are each—(CH₂)₄—Y² and Y² is —NH₃ ⁺.
 25. The compound of claim 22, wherein X¹and X² are each H.
 26. The compound of claim 22, wherein A and B are thesame and selected from the group consisting of RvD1, RvD2, RvE1, LXA4,PDX, AT-RvD1, AT-RvD2, AT-RvE1, and AT-LXA4.
 27. The compound of claim26, wherein A and B are selected from the group consisting of RvE1,LXA4, AT-RvE1, and AT-LXA4.
 28. The compound of claim 27, wherein A andB are selected from RvE1 or LXA4
 29. The compound of claim 22, which isselected from the group consisting of Compounds 1-3, 6-8, 11-13, 16-18,21-23, 26-28, 31-33, and 36-38 of Table
 5. 30. The compound of claim 22,which is selected from the group consisting of Compounds 1-3 and 6-8 ofTable
 5. 31. The compound of claim 22, which is selected from the groupconsisting of Compounds 11-13 and 16-18 of Table
 5. 32. A pharmaceuticalcomposition comprising the compound of claim 22, and a carrier orexcipient.
 33. (canceled)
 34. The pharmaceutical composition of claim32, formulated as an oral or rectal dosage form.
 35. (canceled)
 36. Amethod for treating inflammation in a subject in need thereof, themethod comprising administering to the subject the compound of claim 22.37. A method for treating an inflammatory bowel disease (IBD) relateddisease or disorder selected from ulcerative colitis, Crohn's disease,proctitis, pouchitis, Crohn's disease of the pouch, eosinophiliccolitis, lymphocytic colitis, collagenous colitis, diversion colitis,chemical colitis, and ischemic colitis in a subject in need thereof, themethod comprising administering to the subject the compound of claim 22.38. A method for treating a gastrointestinal disease or disorderselected from eosinophilic esophagitis, Behcet's disease, irritablebowel syndrome, Celiac disease, intestinal mucositis, diverticulitis,and short bowel syndrome in a subject in need thereof, the methodcomprising administering to the subject the compound of claim
 22. 39. Amethod for treating ulcerative colitis, Crohn's disease, or pouchitis ina subject in need thereof, the method comprising administering to thesubject the compound of claim
 22. 40. (canceled)
 41. A method of makinga compound of claim 22, the method comprising contacting a solution ofthe SPM in a nonaqueous solvent, preferably methanol, with an amount ofmagnesium, calcium, or zinc di-lysinate, such that the molar amount ofthe SPM to the metal di-lysinate is about 2:1.
 42. The method of claim41, wherein the solution further comprises an antioxidant, preferablytocopherol.